Sulfoximines as kinase inhibitors

ABSTRACT

The present invention relates to organic molecules capable of modulating tyrosine kinase signal transduction in order to regulate, modulate and/or inhibit abnormal cell proliferation.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is based on, and claims the benefit of, U.S.Provisional Application No. 60/866,080, filed Nov. 16, 2006, and whichis incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel compounds capable of modulating,regulating and/or inhibiting tyrosine kinase signal transduction. Thepresent invention is also directed to methods of regulating, modulatingor inhibiting tyrosine kinases, whether of the receptor or non-receptorclass, for the prevention and/or treatment of disorders related tounregulated tyrosine kinase signal transduction, including cell growth,metabolic, and blood vessel proliferative disorders.

2. Description of the Related Art

Protein tyrosine kinases (PTKs) comprise a large and diverse class ofproteins having enzymatic activity. The PTKs play an important role inthe control of cell growth and differentiation.

For example, receptor tyrosine kinase mediated signal transduction isinitiated by extracellular interaction with a specific growth factor(ligand), followed by receptor dimerization, transient stimulation ofthe intrinsic protein tyrosine kinase activity and phosphorylation.Binding sites are thereby created for intracellular signal transductionmolecules and lead to the formation of complexes with a spectrum ofcytoplasmic signaling molecules that facilitate the appropriate cellularresponse (e.g., cell division, metabolic homeostasis, and responses tothe extracellular microenvironment).

With respect to receptor tyrosine kinases, it has been shown also thattyrosine phosphorylation sites function as high-affinity binding sitesfor SH2 (src homology) domains of signaling molecules. Severalintracellular substrate proteins that associate with receptor tyrosinekinases (RTKs) have been identified. They may be divided into twoprincipal groups: (1) substrates which have a catalytic domain; and (2)substrates which lack such domain but serve as adapters and associatewith catalytically active molecules. The specificity of the interactionsbetween receptors or proteins and SH2 domains of their substrates isdetermined by the amino acid residues immediately surrounding thephosphorylated tyrosine residue. Differences in the binding affinitiesbetween SH2 domains and the amino acid sequences surrounding thephosphotyrosine residues on particular receptors are consistent with theobserved differences in their substrate phosphorylation profiles. Theseobservations suggest that the function of each receptor tyrosine kinaseis determined not only by its pattern of expression and ligandavailability but also by the array of downstream signal transductionpathways that are activated by a particular receptor. Thus,phosphorylation provides an important regulatory step which determinesthe selectivity of signaling pathways recruited by specific growthfactor receptors, as well as differentiation factor receptors.

Aberrant expression or mutations in the PTKs have been shown to lead toeither uncontrolled cell proliferation (e.g. malignant tumor growth) orto defects in key developmental processes. Consequently, the biomedicalcommunity has expended significant resources to discover the specificbiological role of members of the PTK family, their function indifferentiation processes, their involvement in tumorigenesis and inother diseases, the biochemical mechanisms underlying their signaltransduction pathways activated upon ligand stimulation and thedevelopment of novel drugs.

Tyrosine kinases can be of the receptor-type (having extracellular,transmembrane and intracellular domains) or the non-receptor type (beingwholly intracellular).

The RTKs comprise a large family of transmembrane receptors with diversebiological activities. The intrinsic function of RTKs is activated uponligand binding, which results in phosphorylation of the receptor andmultiple cellular substrates, and subsequently in a variety of cellularresponses.

At present, at least nineteen (19) distinct RTK subfamilies have beenidentified. One RTK subfamily, designated the HER subfamily, is believedto be comprised of EGFR, HER2, HER3 and HER4. Ligands to the Hersubfamily of receptors include epithelial growth factor (EGF), TGF-α,amphiregulin, HB-EGF, betacellulin and heregulin.

A second family of RTKs, designated the insulin subfamily, is comprisedof the INS-R, the IGF-1R and the IR-R. A third family, the “PDGF”subfamily includes the PDGF α and β receptors, CSFIR, c-kit and FLK-II.Another subfamily of RTKs, identified as the FLK family, is believed tobe comprised of the Kinase insert Domain-Receptor fetal liver kinase-1(KDR/FLK-1), the fetal liver kinase 4 (FLK-4) and the fins-like tyrosinekinase 1 (flt-1). Each of these receptors was initially believed to bereceptors for hematopoietic growth factors. Two other subfamilies ofRTKs have been designated as the FGF receptor family (FGFR1, FGFR2,FGFR3 and FGFR4) and the Met subfamily (c-met and Ron).

Because of the similarities between the PDGF and FLK subfamilies, thetwo subfamilies are often considered together. The known RTK subfamiliesare identified in Plowman et al, 1994, DN&P 7(6): 334-339, which isincorporated herein by reference.

The non-receptor tyrosine kinases represent a collection of cellularenzymes which lack extracellular and transmembrane sequences. Atpresent, over twenty-four individual non-receptor tyrosine kinases,comprising eleven (11) subfamilies (Src, Frk, Btk, Csk, Abl, Zap70,Fes/Fps, Fak, Jak, Ack and LIMK) have been identified. At present, theSrc subfamily of non-receptor tyrosine kinases is comprised of thelargest number of PTKs and include Src, Yes, Fyn, Lyn, Lck, Blk, Hck,Fgr and Yrk. The Src subfamily of enzymes has been linked tooncogenesis. A more detailed discussion of non-receptor tyrosine kinasesis provided in Bolen, 1993, Oncogen 8: 2025-2031, which is incorporatedherein by reference.

Many of the tyrosine kinases, whether an RTK or non-receptor tyrosinekinase, have been found to be involved in cellular signaling pathwaysleading to cellular signal cascades leading to pathogenic conditions,including cancer, psoriasis and hyper immune response.

In view of the surmised importance of PTKs to the control, regulationand modulation of cell proliferation the diseases and disordersassociated with abnormal cell proliferation, many attempts have beenmade to identify receptor and non-receptor tyrosine kinase “inhibitors”using a variety of approaches, including the use of mutant ligands (U.S.Pat. No. 4,966,849), soluble receptors and antibodies (PCT ApplicationNo. WO 94/10202; Kendall & Thomas, 1994, Proc. Nat'l Acad. Sci. 90:10705-09; Kim, et al, 1993, Nature 362: 841-844), RNA ligands (Jellinek,et al, Biochemistry 33: 10450-56); Takano, et al, 1993, Mol. Bio. Cell4:358A; Kinsella, et al, 1992, Exp. Cell Res. 199: 56-62; Wright, et al,1992, J. Cellular Phys. 152: 448-57) and tyrosine kinase inhibitors (PCTApplication Nos. WO 94/03427; WO 92/21660; WO 91/15495; WO 94/14808;U.S. Pat. No. 5,330,992; Mariani, et al, 1994, Proc. Am. Assoc. CancerRes. 35: 2268).

More recently, attempts have been made to identify small molecules whichact as tyrosine kinase inhibitors. For example, bis monocyclic, bicyclicor heterocyclic aryl compounds (PCT Application No. WO 92/20642),vinylene-azaindole derivatives (PCT Application No. WO 94/14808) and1-cyclopropyl-4-pyridyl-quinolones (U.S. Pat. No. 5,330,992) have beendescribed generally as tyrosine kinase inhibitors. Styryl compounds(U.S. Pat. No. 5,217,999), styryl-substituted pyridyl compounds (U.S.Pat. No. 5,302,606), certain quinazoline derivatives (EP Application No.0 566 266 A1), seleoindoles and selenides (PCT Application No. WO94/03427), tricyclic polyhydroxylic compounds (PCT Application No. WO92/21660) and benzylphosphonic acid compounds (PCT Application No. WO91/15495) have been described as compounds for use as tyrosine kinaseinhibitors for use in the treatment of cancer.

The identification of effective small compounds which specificallyinhibit signal transduction by modulating the activity of receptor andnon-receptor tyrosine kinases to regulate and modulate abnormal orinappropriate cell proliferation is therefore desirable and one objectof this invention.

In addition, certain small compounds are disclosed in U.S. Pat. Nos.5,792,783; 5,834,504; 5,883,113; 5,883,116 and 5,886,020 as useful forthe treatment of diseases related to unregulated TKS transduction. Seealso patents and PCT Published Patent Application WO 02/29630; U.S. Pat.Nos. 6,599,173; 6,765,012; 6,699,863; 6,541,504 and 6,747,025. Thesepatents are hereby incorporated by reference in its entirety for thepurpose of disclosing starting materials and methods for the preparationthereof, screens and assays to determine a claimed compound's ability tomodulate, regulate and/or inhibit cell proliferation, indications whichare treatable with said compounds, formulations and routes ofadministration, effective dosages, etc.

BRIEF SUMMARY OF THE INVENTION

The present invention relates to organic molecules capable ofmodulating, regulating and/or inhibiting tyrosine kinase signaltransduction. Such compounds are useful for the treatment of diseasesrelated to unregulated TKS transduction, including cell proliferativediseases such as cancer, atherosclerosis, restenosis, metabolic diseasessuch as diabetes, inflammatory diseases such as psoriasis and chronicobstructive pulmonary disease, vascular proliferative disorders such asdiabetic retinopathy, age-related macular degeneration and retinopathyof prematurity, autoimmune diseases and transplant rejection.

In one illustrative embodiment, the compounds of the present inventionhave the following general formula I:

wherein:

-   -   X is CR⁴ or N;    -   Y is CR¹ or N;    -   R¹ is selected from the group consisting of hydrogen, alkyl,        halogen, OR⁴, CN, NO₂, COR⁴, (CH²)_(a)OR⁴, (CH₂)_(a)N(R⁴)₂,        C(O)N(R⁴)₂ and N(R⁴)₂;    -   R² is selected from the group consisting of hydrogen, halogen,        alkyl, OR⁴, CN, NO₂, SO₂N(R⁴)₂, COR⁴, (CH₂)_(a)OR⁴,        (CH₂)_(a)N(R⁴)₂, C(O)N(R⁴)₂, N(R⁴)₂ and N(R⁶)(CR⁷R⁸)_(a)R¹⁰;    -   R³ is selected from the group consisting of hydrogen, halogen,        alkyl, OR⁴, CN, NO₂, SO₂N(R⁴)₂, COR⁴, (CH₂)_(a)OR⁴,        (CH₂)_(a)N(R⁴)₂, C(O)N(R⁴)₂, N(R⁴)₂ and N(R⁶)(CR⁷R⁸)_(a)R¹⁰;    -   R⁴ is hydrogen or C₁ to C₄ alkyl;    -   A is selected from the group consisting of C≡C, CH═CH, CH₂CH₂,        CH₂O, CF₂O, OCH₂, OCF₂, O, N(R⁴), C(O), S(O)_(e), NR⁷C(O),        C(O)NR⁷ and N(R⁷)C(O)NR⁷;    -   B is selected from the group consisting of hydrogen, alkyl and        alkyloxyalkyl or B may be a 5 or 6 membered carbocyclic aryl or        heterocyclic aryl group;    -   E is a 5 or 6 membered carbocyclic aryl or heterocyclic aryl        group;    -   E′ is selected from the group consisting of alkyl, CF₃,

-   (CR⁷R⁸)_(a)C(O)OR¹⁰, (CR⁷R⁸)_(a)C(O)N(R¹⁰)₂,    (CR⁷R⁸)_(a)C(O)N(OR¹⁰)(R¹⁰), (CR⁷R⁸)_(a)(OR¹⁰), (CR⁷R⁸)_(a)N(R¹⁰)₂,    and (CR⁷R⁸)_(a)R¹⁰; wherein R⁷ and R⁸ are selected from the group    consisting of H, halogen, hydroxyl, and alkyl or CR⁷R⁸ may represent    a carbocyclic ring of from 3 to 6 carbons; and

-   R¹⁰ is selected from the group consisting of hydrogen, halogen,    alkyl, hydroxyl, hydroxymethyl, carbocyclic aryl, heterocyclic aryl,    (CR⁷R⁸)_(a)C(O)OR⁶, (CR⁷R⁸)_(a)C(O)R⁶, (CR⁷R⁸)_(a)C(O)N(R⁶)₂,    (CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶), (CR⁷R⁸)_(a)(OR⁶), (CR⁷R⁸)_(a)N(R⁶)₂ and    (CR⁷R⁸)_(a)R⁶, wherein R⁶ is selected from the group consisting of    hydrogen, carboalkyl, alkylamine, alkylhydroxy, and alkyloxyalkyl or    R⁶ is a 5 or 6 membered carbocyclic or heterocyclic group;

a is 0 or an integer of from 1 to 5;

b is an integer of from 2 to 5;

c is 0 or an integer of from 1 to 4;

d is 0 or an integer of from 1 to 5;

e is 0 or an integer of from 1 to 2 and further including prodrugs,pharmaceutically acceptable salts, racemic mixtures and enantiomers ofsaid compound.

Preferably, B is a carbocyclic aryl or heterocyclic aryl represented byformula II below:

wherein said carbocyclic aryl and heterocyclic aryl groups are selectedfrom the group consisting of:

wherein R is selected from the group consisting of halogen, alkyl, CF₃,OCF₃, OCF₂H, CH₂CN, CN, SR⁶, OP(O)(OR⁶)₂, OCH₂O, HC═N—NH, N═CH—S,(CR⁷R⁸)_(a)C(O)R⁶, O(CR⁷R⁸)_(a)C(O)R⁶, N(R⁶)(CR⁷R⁸)_(a)C(O)R⁶,C(O)(CR⁷R⁸)_(a)C(O)R⁶, S(O)_(e)(CR⁷R⁸)_(a)C(O)R⁶, (CR⁷R⁸)_(a)C(O)OR⁶,O(CR⁷R⁸)_(a)C(O)OR⁶, N(R⁶)(CR⁷R⁸)_(a)C(O)OR⁶, C(O)(CR⁷R⁸)_(a)C(O)OR⁶,S(O)_(e)(CR⁷R⁸)_(a)C(O)OR⁶, (CR⁷R⁸)_(a)C(O)N(R⁶)₂,O(CR⁷R⁸)_(a)C(O)N(R⁶)₂, N(R⁶)(CR⁷R⁸)_(a)C(O)N(R⁶)₂,C(O)(CR⁷R⁸)_(a)C(O)N(R⁶)₂, S(O)_(e)(CR⁷R⁸)_(a)C(O)N(R⁶)₂,(CR⁷R⁸)_(a)N(R⁶)C(O)N(R⁶)₂, O(CR⁷R⁸)_(b)N(R⁶)C(O)N(R⁶)₂,N(R⁶)(CR⁷R⁸)_(b)N(R⁶)C(O)N(R⁶)₂, C(O)(CR⁷R⁸)_(a)N(R⁶)C(O)N(R⁶)₂,S(O)_(e)(CR⁷R⁸)_(a)N(R⁶)C(O)N(R⁶)₂, (CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶),O(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶), N(R⁶)(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶),C(O)(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶), S(O)_(e)(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶),(CR⁷R⁸)_(a)(OR⁶), O(CR⁷R⁸)_(a)(OR⁶), N(R⁶)(CR⁷R⁸)_(a)(OR⁶), C(O)(CR⁷R⁸)_(a)(OR⁶), S(O)_(a)(CR⁷R⁸)_(a)(OR⁶), (CR⁷R⁸)N(R⁶)₂,O(CR⁷R⁸)_(b)N(R⁶)₂, N(R⁶)(CR⁷R⁸)_(b)N(R⁶)₂, C(O)(CR⁷R⁸)_(a)N(R⁶)₂,S(O)_(e)(CR⁷R⁸)_(a)N(R⁶)₂, (CR⁷R⁸)_(a)R⁶, O(CR⁷R⁸)_(a)R⁶,N(R⁶)(CR⁷R⁸)_(a)R⁶, C(O)(CR⁷R⁸)_(a)R⁶ and, S(O)_(e)(CR⁷R⁸)_(a)R⁶.

Most preferably R⁶ is selected from the group consisting of hydrogen,alkyl, dilower alkyl amine or a heterocyclic group represented by thelist below or N(R⁶)₂ may represent a 3 to 7 membered heterocyclic group,

wherein R⁵ is hydrogen, halogen, simple alkyl, CF₃, hydroxyl, OR⁷,N(R⁷)₂ or NO2.

Preferably, E is a 5 or 6 membered carbocyclic aryl or heterocyclic arylrepresented by formula III below:

wherein said carbocyclic aryl and heterocyclic aryl is selected from thegroup consisting of:

Compounds of formula I below are useful as kinase inhibitors. As suchcompounds of formula I will be useful for treating diseases related tounregulated tyrosine kinase signal transduction, for example, cancer,blood vessel proliferative disorders, fibrotic disorders, andneurodegenerative diseases. In particular compounds of the presentinvention are useful for treatment of mesangial cell proliferativedisorders and metabolic diseases, diabetic retinopathy, age-relatedmacular degeneration, retinopathy of prematurity, arthritis, restenosis,hepatic cirrhosis, atherosclerosis, psoriasis, diabetes mellitus, woundhealing, inflammation and neurodegenerative diseases.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is further directed to pharmaceutical compositionscomprising a pharmaceutically effective amount of the above-describedcompounds and a pharmaceutically acceptable carrier or excipient. Such acomposition is believed to modulate signal transduction by a tyrosinekinase, either by inhibition of catalytic activity, affinity to ATP orability to interact with a substrate.

More particularly, the compositions of the present invention may beincluded in methods for treating diseases comprising proliferation,fibrotic or metabolic disorders, for example cancer, fibrosis,psoriasis, atherosclerosis, arthritis, and other disorders related toabnormal vasculogenesis and/or angiogenesis, such as diabeticretinopathy.

The following defined terms are used throughout this specification:

“Me” refers to methyl.

“Et” refers to ethyl.

“tBu” refers to t-butyl.

“iPr” refers to i-propyl.

“Ph” refers to phenyl.

“Pharmaceutically acceptable salt” refers to those salts which retainthe biological effectiveness and properties of the free bases and whichare obtained by reaction with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid and the like.

“Alkyl” refers to a straight-chain, branched or cyclic saturatedaliphatic hydrocarbon. Preferably, the alkyl group has 1 to 12 carbons.More preferably, it is a lower alkyl of from 1 to 7 carbons, mostpreferably 1 to 4 carbons. Typical alkyl groups include methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl andthe like. The alkyl group may be optionally substituted with one or moresubstituents are selected from the group consisting of hydroxyl, cyano,alkoxy, ═O, ═S, NO₂, halogen, dimethyl amino, and SH.

“Alkenyl” refers to a straight-chain, branched or cyclic unsaturatedhydrocarbon group containing at least one carbon-carbon double bond.Preferably, the alkenyl group has 1 to 12 carbons. More preferably it isa lower alkenyl of from 1 to 7 carbons, most preferably 1 to 4 carbons.The alkenyl group may be optionally substituted with one or moresubstituents selected from the group consisting of hydroxyl, cyano,alkoxy, ═O, ═S, NO₂, halogen, dimethyl amino, and SH.

“Alkynyl” refers to a straight-chain, branched or cyclic unsaturatedhydrocarbon containing at least one carbon-carbon triple bond.Preferably, the alkynyl group has 1 to 12 carbons. More preferably it isa lower alkynyl of from 1 to 7 carbons, most preferably 1 to 4 carbons.The alkynyl group may be optionally substituted with one or moresubstituents selected from the group consisting of hydroxyl, cyano,alkoxy, ═O, ═S, NO₂, halogen, dimethyl amino, and SH.

“Alkoxyl” refers to an “O-alkyl” group.

“Aryl” refers to an aromatic group which has at least one ring having aconjugated pi electron system and includes carbocyclic aryl,heterocyclic aryl and biaryl groups. The aryl group may be optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, trihalomethyl, hydroxyl, SH, OH, NO₂, amine,thioether, cyano, alkoxy, alkyl, and amino.

“Alkaryl” refers to an alkyl that is covalently joined to an aryl group.Preferably, the alkyl is a lower alkyl.

“Carbocyclic ring” refers to a substituted or unsubstituted cyclicradical, including cycloalkyl, cycloalkenyl and carbocyclic aryl whereinthe ring atoms are carbon and said substituents are selected from thegroup consisting of hydroxyl, cyano, alkoxy, ═O, ═S, NO₂, halogen,dimethyl amino, and SH.

“Carbocyclic aryl” refers to an aryl group wherein the ring atoms arecarbon.

“Heterocyclic ring” refers to a substituted or unsubstituted cyclicradical including cycloalkyl, cycloalkenyl and heterocyclic aryl wherein1 to 3 of the ring atoms are heteroatoms and the remainder of the ringatoms are carbon substituents are selected from the group consisting ofhydroxyl, cyano, alkoxy, ═O, ═S, NO₂, halogen, dimethyl amino, and SH.

“Heterocyclic aryl” refers to an aryl group having from 1 to 3heteroatoms as ring atoms, the remainder of the ring atoms being carbon.Heteroatoms include oxygen, sulfur, and nitrogen. Thus, heterocyclicaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkylpyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like.

“Hydrocarbyl” refers to a hydrocarbon radical having only carbon andhydrogen atoms. Preferably, the hydrocarbyl radical has from 1 to 20carbon atoms, more preferably from 1 to 12 carbon atoms and mostpreferably from 1 to 7 carbon atoms.

“Substituted hydrocarbyl” refers to a hydrocarbyl radical wherein one ormore, but not all, of the hydrogen and/or the carbon atoms are replacedby a halogen, nitrogen, oxygen, sulfur or phosphorus atom or a radicalincluding a halogen, nitrogen, oxygen, sulfur or phosphorus atom, e.g.fluoro, chloro, cyano, nitro, hydroxyl, phosphate, thiol, etc.

“Amide” refers to —C(O)—NH—R′, wherein R′ is alkyl, aryl, alkylaryl orhydrogen.

“Thioamide” refers to —C(S)—NH—R′, wherein R′ is alkyl, aryl, alkylarylor hydrogen.

“Amine” refers to a —N(R″)R′″ group, wherein R″ and R′″ areindependently selected from the group consisting of alkyl, aryl, andalkylaryl.

“Thioether” refers to —S—R″, wherein R″ is alkyl, aryl, or alkylaryl.

“Sulfonyl” refers to —S(O)₂—R″″, where R″″ is aryl, C(CN)═C-aryl, CH₂CN,alkylaryl, sulfonamide, NH-alkyl, NH-alkylaryl, or NH-aryl.

The compounds of this invention may be prepared by the general schemeset forth in Scheme 1.

In particular the compounds of the present invention are selected fromthe compounds of Table 1, Table 2 and Table 2.1 below. In table 1 thecompounds of the present invention are exemplified by any combination ofAr¹ and R² attached to the core template illustrated.

TABLE 1

Ar¹ Substitution

R² Substitution

TABLE 2 Example Number Structure Example 423

Example 424

Example 425

Example 426

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TABLE 2-1 Example # Structure 476

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The present invention relates to compounds capable of regulating and/ormodulating tyrosine kinase signal transduction and more particularlyreceptor and non-receptor tyrosine kinase signal transduction.

Receptor tyrosine kinase mediated signal transduction is initiated byextracellular interaction with a specific growth factor (ligand),followed by receptor dimerization, transient stimulation of theintrinsic protein tyrosine kinase activity and phosphorylation. Bindingsites are thereby created for intracellular signal transductionmolecules and lead to the formation of complexes with a spectrum ofcytoplasmic signaling molecules that facilitate the appropriate cellularresponse (e.g., cell division, metabolic effects and responses to theextracellular microenvironment).

It has been shown that tyrosine phosphorylation sites in growth factorreceptors function as high-affinity binding sites for SH2 (src homology)domains of signaling molecules. Several intracellular substrate proteinsthat associate with receptor tyrosine kinases have been identified. Theymay be divided into two principal groups: (1) substrates which have acatalytic domain; and (2) substrates which lack such domain but serve asadapters and associate with catalytically active molecules. Thespecificity of the interactions between receptors and SH2 domains oftheir substrates is determined by the amino acid residues immediatelysurrounding the phosphorylated tyrosine residue. Differences in thebinding affinities between SH2 domains and the amino acid sequencessurrounding the phosphotyrosine residues on particular receptors areconsistent with the observed differences in their substratephosphorylation profiles. These observations suggest that the functionof each receptor tyrosine kinase is determined not only by its patternof expression and ligand availability but also by the array ofdownstream signal transduction pathways that are activated by aparticular receptor. Thus, phosphorylation provides an importantregulatory step which determines the selectivity of signaling pathwaysrecruited by specific growth factor receptors, as well asdifferentiation factor receptors.

Tyrosine kinase signal transduction results in, among other responses,cell proliferation, differentiation and metabolism. Abnormal cellproliferation may result in a wide array of disorders and diseases,including the development of neoplasia such as carcinoma, sarcoma,leukemia, glioblastoma, hemangioma, psoriasis, arteriosclerosis,arthritis and diabetic retinopathy (or other disorders related touncontrolled angiogenesis and/or vasculogenesis, e.g. maculardegeneration).

This invention is therefore directed to compounds which regulate,modulate and/or inhibit tyrosine kinase signal transduction by affectingthe enzymatic activity of the RTKs and/or the non-receptor tyrosinekinases and interfering with the signal transduced such proteins. Moreparticularly, the present invention is directed to compounds whichregulate, modulate and/or inhibit the RTK and/or non-receptor tyrosinekinase mediated signal transduction pathways as a therapeutic approachto cure many kinds of solid tumors, including but not limited tocarcinoma, sarcoma, leukemia, erythroblastoma, glioblastoma, meningioma,astrocytoma, melanoma and myoblastoma. Indications may include, but arenot limited to brain cancers, bladder cancers, ovarian cancers, gastriccancers, pancreas cancers, colon cancers, blood cancers, lung cancersand bone cancers.

Biological data for the compounds of the present invention was generatedby use of the following assays.

VEGF Stimulated Ca⁺⁺ Signal in vitro

Automated FLIPR (Fluorometric Imaging Plate Reader) technology was usedto screen for inhibitors of VEGF induced increases in intracellularcalcium levels in fluorescent dye loaded endothelial cells. HUVEC (humanumbilical vein endothelial cells) (Clonetics) were seeded in 96-wellfibronectin coated black-walled plates overnight @37° C./5% CO2. Cellswere loaded with calcium indicator Fluo-4 for 45 minutes at 37° C. Cellswere washed 4 times (Original Cell Wash, Labsystems) to removeextracellular dye. For screening, cells were pre-incubated with testagents for 30 minutes, at a single concentration (10 uM) or atconcentrations ranging from 0.01 to 10.0 uM followed by VEGF stimulation(5 ng/mL). Changes in fluorescence at 516 nm were measuredsimultaneously in all 96 wells using a cooled CCD camera. Data weregenerated by determining max-min fluorescence levels for unstimulated,stimulated, and drug treated samples. IC₅₀ values for test compoundswere calculated from % inhibition of VEGF stimulated responses in theabsence of inhibitor.

Protocol for KDR Assay:

The cytoplasmic domain of the human VEGF receptor (VEGFR-2) wasexpressed as a Histidine-tagged fusion protein following infection ofinsect cells using an engineered baculovirus. His-VEGFR-2 was purifiedto homogeneity, as determined by SDS-PAGE, using nickel resinchromatography. Kinase assays were performed in 96 well microtiterplates that were coated overnight with 30 μg of poly-Glu-Tyr (4:1) in 10mM Phosphate Buffered Saline (PBS), pH 7.2-7.4. The plates wereincubated with 1% BSA and then washed four times with PBS prior tostarting the reaction. Reactions were carried out in 120 μL reactionvolumes containing 3.6 μM ATP in kinase buffer (50 mM Hepes buffer pH7.4, 20 mM MgCl₂, 0.1 mM MnCl₂ and 0.2 mM Na₃VO₄). Test compounds werereconstituted in 100% DMSO and added to the reaction to give a finalDMSO concentration of 5%. Reactions were initiated by the addition 0.5ng of purified protein. Following a ten minute incubation at 25° C., thereactions were washed four times with PBS containing 0.05% Tween-20. 100μl of a monoclonal anti-phosphotyrosine antibody-peroxidase conjugatewas diluted 1:10000 in PBS-Tween-20 and added to the wells for 30minutes. Following four washes with PBS-Tween-20, 100 μl ofO-Phenylenediamine Dihydrochloride in Phosphate-citrate buffer,containing urea hydrogen peroxide, was added to the wells for 7 minutesas a colorimetric substrate for the peroxidase. The reaction wasterminated by the addition of 100 μl of 2.5NH₂SO₄ to each well and readusing a microplate ELISA reader set at 492 nm. IC₅₀ values for compoundinhibition were calculated directly from graphs of optical density(arbitrary units) versus compound concentration following subtraction ofblank values.

The invention is further illustrated by the following non-limitingexamples.

EXAMPLE 1N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(phenylethynyl)nicotinamideStep 1—Representative Procedure for the Preparation of Sulfoxides Methylphenyl sulfoxide

To a stirred suspension of iodoxybenzoic acid (3.7 g, 13.2 mmol, 1.1 eq)in 100:1 CHCl₃/H₂O (25 mL) was added tetraethylammonium bromide (TEAB)(126 mg, 5 mol %), followed by the addition of p-tolyl sulfide (1.66 g,12 mmol) in one portion. The mixture was stirred at room temperature forapproximately 30 minutes until consumption of sulfide was observed (TLC,hexanes/EtOAc 1/1). The residual solids were removed by filtration andwashed with CHCl₃ (40 mL). The combined filtrate was washed successivelywith saturated aq. NaHCO₃ (30 mL), saturated aq. NaCl (30 mL), driedover sodium sulfate, and concentrated to provide the crude product.Purification by silica gel column chromatography (50% hexanes/EtOAcelution) afforded the title compound (1.68 g, yield 91%). ¹H NMR (300MHz, CDCl₃) δ 7.52 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H), 2.71 (s,3H), 2.42 (s, 3H); ESI-MS m/z 154.7 (M+H)⁺.

Step 2—Representative Procedure for the Preparation of SubstitutedSulfoximinesS-methyl-S-(4-methoxyphenyl)-N-[[2-(trimethylsilyl)ethyl]sulfonyl]sulfoximine

To a solution of 1-methanesulfinyl-4-methoxy-benzene (1.51 g, 8.88 mmol)in dry acetonitrile (35 mL), was added CuPF₆(CH₃CN)₄ (165 mg, 0.44 mmol,0.05 eq.). The mixture was cooled to 0° C. and[N-(2-(trimethylsilyl)ethanesulfonyl)imino]phenyl-iodinate (3.75 g, 9.8mmol, 1.1 eq.) (prepared by the method described in J. Org. Chem. 1999,64, 5304-5307) was added. The reaction mixture was allowed to warm toroom temperature, stirred for 20 h and the solvent then evaporated. Theresidue was dissolved in EtOAc (50 mL) and filtered through a pad ofsilica gel. The ethyl acetate solution was evaporated and the residuewas triturated with hexanes to provide the title compound as a whitesolid (3.0 g, recovery 96%, purity >95% by HPLC). If required, thecompound can be further purified by silica gel column chromatography(50% hexanes/EtOAc). ¹H NMR (300 MHz, CDCl₃) δ 7.95 (d, J=9.0 Hz, 2H),7.05 (d, J=9.0 Hz, 2H), 3.89 (s, 3H), 3.41 (s, 3H), 3.16-3.10 (m, 2H),1.18-1.12 (m, 2H), 0.04 (s, 9H); ESI-MS m/z 349.9 (M+H)⁺.

Step 3—Representative Procedure for the Deprotection of(trimethylsilyl)ethyl]sulfonyl Substituted SulfoximinesS-(4-methoxyphenyl)-S-methyl-sulfoximine

A mixture ofS-methyl-S-(4-methoxyphenyl)-N-[[2-(trimethylsilyl)ethyl]sulfonyl]-sulfoximine(2.9 g, 8.3 mmol) and 1.0 M of TBAF (12.5 mL, 12.5 mmol, 1.5 eq.) washeated in a microwave at 120° C. for 20 minutes. After cooling to roomtemperature, the solvent was evaporated and the resulting mixture waspurified by silica gel column chromatography (elution with 100% EtOAc)to provide the title compound (1.46 g, yield 96%). ¹H NMR (300 MHz,CDCl₃) δ 7.92 (d, J=9.0 Hz, 2H), 6.99 (d, J=9 Hz, 2H), 3.87 (s, 3H),3.08 (s, 3H); ESI-MS m/z 186.1 (M+H)⁺.

Step 4—Representative Procedure for the Sonagashira Reaction of ethyl5-bromonicotinate with acetylenes 5-Phenylethynyl-nicotinic acid ethylester

To a solution of ethyl 5-bromonicotinate (1.15 g, 5 mmol) in ethylacetate (20 mL) under an N₂ atmosphere, was added triethylamine (1.1 mL,7.5 mmol, 1.5 eq.), phenyl acetylene (0.766 g, 7.5 mmol, 1.5 eq.),dichloro-bis(triphenylphosphine)-palladium(II) (176 mg, 0.25 mmol, 0.05eq.), and copper iodide (10 mg, 0.05 mmol, 0.01 eq). The reactionmixture was heated at 50° C. for 20 h before being cooled to roomtemperature, filtered through a pad of celite, and solvent evaporated toprovide a dark brown oil. Silica gel column chromatography (9/1-4/1hexanes/EtOAc elution) provided the title compound as a pale yellow oil(1.26 g, yield 100%). ¹H NMR (300 MHz, CDCl₃) δ 9.11 (d, J=1.8 Hz, 1H),8.87 (d, J=2.1 Hz, 1H), 8.39 (dd, J=1.8, 2.1 Hz, 1H), 7.56-7.53 (m, 2H),7.40-7.30 (m, 3H), 4.42 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H);ESI-MS m/z 251.9 (M+H)⁺.

Step 5—Representative Procedure for Nicotinic Acid Ester Hydrolysis5-Phenylethynyl-nicotinic acid

To a solution of 5-phenylethynyl-nicotinic acid ethyl ester (1.17 g,4.64 mmol) in methanol (10 mL) was added 5 N aqueous sodium hydroxide (2mL, 10 mmol). The mixture was stirred at room temperature forapproximately 20 h, before the reaction mixture was diluted with water(3 mL) and extracted with hexanes/EtOAc (95/5) (10 mL). The aqueoussolution was acidified with 1 N HCl to pH 4. The white precipitate thatformed was collected by filtration, washed with water (2 mL), and driedunder vacuum to provide the title compound as a white solid (987 mg,yield 95%). ¹H NMR (300 MHz, d₆-DMSO) δ 9.02 (d, J=1.8 Hz, 1H), 8.94 (d,J=2.4 Hz, 1H), 8.34 (dd, J=1.8, 2.4 Hz, 1H), 7.63-7.60 (m, 2H),7.48-7.44 (m, 3H); ESI-MS m/z 223.9 (M+H)⁺.

Step 6—Representative Procedure for Coupling of SubstitutedSulfoximine's to Substituted Nicotinic AcidsN-[1-(4-Methoxy-phenyl)-methylsulfoximine]-5-phenylethynyl-nicotinamide

A solution of 5-phenylethynyl-nicotinic acid (0.1 mmol) andS-(4-methoxyphenyl)-S-methyl-sulfoximine (0.1 mmol),1-hydroxybenzotriazole (0.15 mmol) in dimethylformamide (1.5 mL) wastreated with 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (0.15 mmol)in dimethylformamide (1.5 mL). The reaction mixture was shaken at roomtemperature for 20 hours and concentrated. The residue was purified byhigh pressure liquid chromatography (phenomenex Luna C18 5 μm column,gradient elution, acetonitrile/10 mM aqueous ammonium carbonate) andconcentrated to give the title compound.

EXAMPLES 2-422

Examples 2 through 422 (table 5) were prepared by the methods describedin Example 1 by employing appropriate combinations of the aryl sulfidesillustrated in table 3 and the acetylenes illustrated in table 4.

TABLE 3 Aryl Sulfide Reagents CAS CAS Number Reagent Number Reagent623-13-2 METHYL P-TOLYL SULFIDE 68121- 3,5- 46-0 DICHLOROTHIOANISOLE1879-16-9 1-METHOXY-4- 3-METHYLTHIOANISOLE (METHYLTHIO)BENZENE 701-57-54-NITROTHIOANISOLE 2388-74-1 3-METHOXY THIOANISOLE 123-09-14-CHLOROTHIOANISOLE 3,4- DIMETHYLTHIOANISOLE 10352-44-04-ACETAMIDOTHIOANISOLE 3,5- DIMETHYLTHIOANISOLE 2524-78-93-ACETAMIDOTHIOANISOLE 100-68-5 THIOANISOLE 4867-37-23-CHLOROTHIOANISOLE 3,4- DIMETHOXYTHIOANISOLE 2524-76-7 3-NITROTHIOANISOLE

TABLE 4 Acetylene Reagents CAS # Reagent CAS # Reagent 126716-PHENYLACETYLENE 15727- 1-ETHYNYLNAPHTHALENE 66-3 65-8 766-97-24-ETHYNYLTOLUENE 121697- 3-ETHYNYLPYRIDINE 66-3 627-41-8 METHYLPROPARGYL ETHER 927-74-2 3-BUTYN-1-OL 917-92-0 3,3-DIMETHYL-1-BUTYNE2561-17-3 3-FLUOROPHENYLACETYLENE 937-31-5 4-NITROPHENYLACETYLENE2510-22-7 4-ETHYNYLPYRIDINE 351002- 4-ETHYNYL-1-FLUORO-2- 766-47-22-ETHYNYLTOLUENE 93-2 METHYLBENZENE 1945- 2-ETHYNYLPYRIDINE 766-81-41-BROMO-3-ETHYNYL-BENZENE 84-2 10401- 3- 766-83-6 3′-CHLOROPHENYLACETYLENE 11-3 HYDROXYPHENYLACETYLENE 129113- 2-ETHYNYL-6- 171290-1-ETHYNYL-3,5- 00-4 METHOXYNAPHTHALENE 52-1 DIMETHOXYBENZENE 768-70-71-ETHYNYL-3- 4302-52-7 3′,4′-DIMETHOXYPHENYL METHOXYBENZENE ACETYLENE768-60- 1-ETH-1-YNYL-4- 767-91-9 1-ETHYNYL-2- 5 METHOXYBENZENEMETHOXYBENZENE 766-96-1 1-BROMO-4- 41876- 4′-N-PIPERIDINOPHENYLETHYNYLBENZENE 66-8 ACETYLENE 4,5-DICHLORO-1-PROP-2- 151361-1-ETHYNYL-3,5-DIFLUORO- YNYLIMIDAZOLE 87-4 BENZENE 873-73-4 1-CHLORO-4-5-ETHYNYL-1-METHYL-1H- ETHYNYLBENZENE IMIDAZOLE 873-31-4 1-CHLORO-2-74331- 1-ETHYNYL-4-METHOXY-2- ETHYNYLBENZENE 69-4 METHYLBENZENE 766-82-5M-TOLYLACETYLENE 74-99-7 PROPYNE 705-31-7 4′-TRIFLUOROMETHYLPHENYL922-67-8 METHYL PROPIOLATE ACETYLENE 766-46-1 1-BROMO-2- 930-51-8CYCLOPENTYLACETYLENE ETHYNYLBENZENE 302912- 1-ETHYNYL-2,4-DIFLUORO-1-ETHYNYL-2- 34-1 BENZENE (TRIFLUOROMETHOXY)BENZENE

TABLE 5 Example Example Name Example 2N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-methylphenyl)ethynyl]nicotinamide Example 3N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(3-methoxyprop-1-yn-1-yl)nicotinamide Example 45-(3,3-dimethylbut-1-yn-1-yl)-N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 5N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-prop-1-yn-1-ylnicotinamide Example 6N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(pyridin-2-ylethynyl)nicotinamide Example 75-[(3-hydroxyphenyl)ethynyl]-N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 85-[(6-methoxy-2-naphthyl)ethynyl]-N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 95-[(3-methoxyphenyl)ethynyl]-N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 105-[(4-methoxyphenyl)ethynyl]-N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 115-[(4-bromophenyl)ethynyl]-N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 125-[3-(4,5-dichloro-1H-imidazol-1-yl)prop-1-yn-1-yl]-N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 135-[(4-chlorophenyl)ethynyl]-N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 145-[(2-chlorophenyl)ethynyl]-N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 15N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3-methylphenyl)ethynyl]nicotinamide Example 16N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-{[4-(trifluoromethyl)phenyl]ethynyl}nicotinamide Example 175-[(2,4-difluorophenyl)ethynyl]-N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 18N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(pyridin-3-ylethynyl)nicotinamide Example 195-[(3-fluorophenyl)ethynyl]-N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 20N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(pyridin-4-ylethynyl)nicotinamide Example 21N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(2-methylphenyl)ethynyl]nicotinamide Example 225-[(3-bromophenyl)ethynyl]-N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 235-[(3-chlorophenyl)ethynyl]-N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 245-[(3,5-dimethoxyphenyl)ethynyl]-N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 255-[(3,4-dimethoxyphenyl)ethynyl]-N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 265-[(2-methoxyphenyl)ethynyl]-N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 27N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-piperidin-1-ylphenyl)ethynyl]nicotinamide Example 285-[(3,5-difluorophenyl)ethynyl]-N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 295-[(4-methoxy-2-methylphenyl)ethynyl]-N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 305-[(4-fluoro-3-methylphenyl)ethynyl]-N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 315-(4-hydroxybut-1-yn-1-yl)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide Example 32N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-(phenylethynyl)nicotinamideExample 33 N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-[(4-methylphenyl)ethynyl]nicotinamide Example 345-(3-methoxyprop-1-yn-1-yl)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide Example 355-(3,3-dimethylbut-1-yn-1-yl)-N-[methyl(oxo)phenyl-λ⁶sulfanylidene]nicotinamide Example 36N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-[(4-nitrophenyl)ethynyl]nicotinamide Example 37N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-prop-1-yn-1-ylnicotinamideExample 38 N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-(pyridin-2-ylethynyl)nicotinamide Example 395-[(3-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide Example 405-[(6-methoxy-2-naphthyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide Example 415-[(3-methoxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide Example 425-[(4-methoxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide Example 435-[(4-bromophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide Example 445-[3-(4,5-dichloro-1H-imidazol-1-yl)prop-1-yn-1-yl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide Example 455-[(4-chlorophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide Example 465-[(2-chlorophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide Example 47N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-[(3-methylphenyl)ethynyl]nicotinamide Example 48N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-{[4-(trifluoromethyl)phenyl]ethynyl}nicotinamide Example 495-[(2-bromophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide Example 505-[(2,4-difluorophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide Example 51N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-(1-naphthylethynyl)nicotinamide Example 52N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-(pyridin-3-ylethynyl)nicotinamide Example 535-[(3-fluorophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide Example 54N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-(pyridin-4-ylethynyl)nicotinamide Example 55N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-[(2-methylphenyl)ethynyl]nicotinamide Example 565-[(3-bromophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide Example 575-[(3-chlorophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide Example 585-[(3,5-dimethoxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide Example 595-[(3,4-dimethoxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide Example 605-[(2-methoxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide Example 61N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-[(4-piperidin-1-ylphenyl)ethynyl]nicotinamide Example 625-[(3,5-difluorophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide Example 635-[(4-methoxy-2-methylphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide Example 645-[(4-fluoro-3-methylphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide Example 655-(4-hydroxybut-1-yn-1-yl)-N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 66N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]-5-[(4-methylphenyl)ethynyl]nicotinamide Example 675-(3-methoxyprop-1-yn-1-yl)-N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 685-(3,3-dimethylbut-1-yn-1-yl)-N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 69N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]-5-[(4-nitrophenyl)ethynyl]nicotinamide Example 70N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]-5-prop-1-yn-1-ylnicotinamide Example 71N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]-5-(pyridin-2-ylethynyl)nicotinamide Example 725-[(3-hydroxyphenyl)ethynyl]-N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 735-[(6-methoxy-2-naphthyl)ethynyl]-N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 745-[(3-methoxyphenyl)ethynyl]-N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 755-[(4-methoxyphenyl)ethynyl]-N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 765-[(4-bromophenyl)ethynyl]-N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 775-[3-(4,5-dichloro-1H-imidazol-1-yl)prop-1-yn-1-yl]-N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 785-[(4-chlorophenyl)ethynyl]-N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 795-[(2-chlorophenyl)ethynyl]-N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 80N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]-5-[(3-methylphenyl)ethynyl]nicotinamide Example 81N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]-5-{[4-(trifluoromethyl)phenyl]ethynyl}nicotinamide Example 825-[(2-bromophenyl)ethynyl]-N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 83N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]-5-(1-naphthylethynyl)nicotinamide Example 84N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]-5-(pyridin-3-ylethynyl)nicotinamide Example 855-[(3-fluorophenyl)ethynyl]-N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 86N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]-5-(pyridin-4-ylethynyl)nicotinamide Example 87N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]-5-[(2-methylphenyl)ethynyl]nicotinamide Example 885-[(3-bromophenyl)ethynyl]-N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 895-[(3-chlorophenyl)ethynyl]-N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 905-[(3,5-dimethoxyphenyl)ethynyl]-N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 915-[(3,4-dimethoxyphenyl)ethynyl]-N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 925-[(2-methoxyphenyl)ethynyl]-N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 935-[(3,5-difluorophenyl)ethynyl]-N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 945-[(1-methyl-1H-imidazol-5-yl)ethynyl]-N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 955-[(4-methoxy-2-methylphenyl)ethynyl]-N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 965-[(4-fluoro-3-methylphenyl)ethynyl]-N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 975-(4-hydroxybut-1-yn-1-yl)-N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 98N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(4-hydroxybut-1-yn-1-yl)nicotinamide Example 99N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(phenylethynyl)nicotinamide Example 100N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-methylphenyl)ethynyl]nicotinamide Example 101N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(3-methoxyprop-1-yn-1-yl)nicotinamide Example 102N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(3,3-dimethylbut-1-yn-1-yl)nicotinamide Example 103N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-nitrophenyl)ethynyl]nicotinamide Example 104N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-prop-1-yn-1-ylnicotinamide Example 105N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(pyridin-2-ylethynyl)nicotinamide Example 106N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3-hydroxyphenyl)ethynyl]nicotinamide Example 107N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3-methoxyphenyl)ethynyl]nicotinamide Example 108N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-methoxyphenyl)ethynyl]nicotinamide Example 1095-[(4-bromophenyl)ethynyl]-N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 110N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[3-(4,5-dichloro-1H-imidazol-1-yl)prop-1-yn-1-yl]nicotinamide Example 1115-[(4-chlorophenyl)ethynyl]-N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 1125-[(2-bromophenyl)ethynyl]-N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 113N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(2,4-difluorophenyl)ethynyl]nicotinamide Example 114N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(1-naphthylethynyl)nicotinamide Example 115N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(pyridin-3-ylethynyl)nicotinamide Example 116N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3-fluorophenyl)ethynyl]nicotinamide Example 117N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(2-methylphenyl)ethynyl]nicotinamide Example 1185-[(3-bromophenyl)ethynyl]-N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 1195-[(3-chlorophenyl)ethynyl]-N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 120N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3,5-dimethoxyphenyl)ethynyl]nicotinamide Example 121N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3,4-dimethoxyphenyl)ethynyl]nicotinamide Example 122N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(2-methoxyphenyl)ethynyl]nicotinamide Example 123N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3,5-difluorophenyl)ethynyl]nicotinamide Example 124N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(1-methyl-1H-imidazol-5-yl)ethynyl]nicotinamide Example 125N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-methoxy-2-methylphenyl)ethynyl]nicotinamide Example 126N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-fluoro-3-methylphenyl)ethynyl]nicotinamide Example 127N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-(4-hydroxybut-1-yn-1-yl)nicotinamide Example 128N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-(phenylethynyl)nicotinamide Example 129N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(4-methylphenyl)ethynyl]nicotinamide Example 130N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-(3-methoxyprop-1-yn-1-yl)nicotinamide Example 131N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-(3,3-dimethylbut-1-yn-1-yl)nicotinamide Example 132N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(4-nitrophenyl)ethynyl]nicotinamide Example 133N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-prop-1-yn-1-ylnicotinamide Example 134N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-(pyridin-2-ylethynyl)nicotinamide Example 135N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(6-methoxy-2-naphthyl)ethynyl]nicotinamide Example 136N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(3-methoxyphenyl)ethynyl]nicotinamide Example 137N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(4-methoxyphenyl)ethynyl]nicotinamide Example 138N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(4-bromophenyl)ethynyl]nicotinamide Example 139N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(4-chlorophenyl)ethynyl]nicotinamide Example 140N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(2-chlorophenyl)ethynyl]nicotinamide Example 141N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(3-methylphenyl)ethynyl]nicotinamide Example 142N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-{[4-(trifluoromethyl)phenyl]ethynyl}nicotinamide Example 143N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(2-bromophenyl)ethynyl]nicotinamide Example 144N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(2,4-difluorophenyl)ethynyl]nicotinamide Example 145N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-(1-naphthylethynyl)nicotinamide Example 146N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-(pyridin-3-ylethynyl)nicotinamide Example 147N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(3-fluorophenyl)ethynyl]nicotinamide Example 148N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-(pyridin-4-ylethynyl)nicotinamide Example 149N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(2-methylphenyl)ethynyl]nicotinamide Example 150N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(3-bromophenyl)ethynyl]nicotinamide Example 151N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(3-chlorophenyl)ethynyl]nicotinamide Example 152N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(3,5-dimethoxyphenyl)ethynyl]nicotinamide Example 153N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(2-methoxyphenyl)ethynyl]nicotinamide Example 154N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(3,5-difluorophenyl)ethynyl]nicotinamide Example 155N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(1-methyl-1H-imidazol-5-yl)ethynyl]nicotinamide Example 156N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(4-methoxy-2-methylphenyl)ethynyl]nicotinamide Example 157N-{[4-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(4-fluoro-3-methylphenyl)ethynyl]nicotinamide Example 158N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-(4-hydroxybut-1-yn-1-yl)nicotinamide Example 159N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-(phenylethynyl)nicotinamide Example 160N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(4-methylphenyl)ethynyl]nicotinamide Example 161N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-(3-methoxyprop-1-yn-1-yl)nicotinamide Example 162N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-(3,3-dimethylbut-1-yn-1-yl)nicotinamide Example 163N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(4-nitrophenyl)ethynyl]nicotinamide Example 164N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-prop-1-yn-1-ylnicotinamide Example 165N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-(pyridin-2-ylethynyl)nicotinamide Example 166N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(3-hydroxyphenyl)ethynyl]nicotinamide Example 167N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(6-methoxy-2-naphthyl)ethynyl]nicotinamide Example 168N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(3-methoxyphenyl)ethynyl]nicotinamide Example 169N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(4-methoxyphenyl)ethynyl]nicotinamide Example 170N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(4-bromophenyl)ethynyl]nicotinamide Example 171N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[3-(4,5-dichloro-1H-imidazol-1-yl)prop-1-yn-1-yl]nicotinamide Example 172N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(4-chlorophenyl)ethynyl]nicotinamide Example 173N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(2-chlorophenyl)ethynyl]nicotinamide Example 174N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(3-methylphenyl)ethynyl]nicotinamide Example 175N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-{[4-(trifluoromethyl)phenyl]ethynyl}nicotinamide Example 176N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(2-bromophenyl)ethynyl]nicotinamide Example 177N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(2,4-difluorophenyl)ethynyl]nicotinamide Example 178N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-(1-naphthylethynyl)nicotinamide Example 179N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-(pyridin-3-ylethynyl)nicotinamide Example 180N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(3-fluorophenyl)ethynyl]nicotinamide Example 181N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-(pyridin-4-ylethynyl)nicotinamide Example 182N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(2-methylphenyl)ethynyl]nicotinamide Example 183N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(3-bromophenyl)ethynyl]nicotinamide Example 184N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(3-chlorophenyl)ethynyl]nicotinamide Example 185N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(3,5-dimethoxyphenyl)ethynyl]nicotinamide Example 186N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(3,4-dimethoxyphenyl)ethynyl]nicotinamide Example 187N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(2-methoxyphenyl)ethynyl]nicotinamide Example 188N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(4-piperidin-1-ylphenyl)ethynyl]nicotinamide Example 189N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(3,5-difluorophenyl)ethynyl]nicotinamide Example 190N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(1-methyl-1H-imidazol-5-yl)ethynyl]nicotinamide Example 191N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(4-methoxy-2-methylphenyl)ethynyl]nicotinamide Example 192N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(4-fluoro-3-methylphenyl)ethynyl]nicotinamide Example 193N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(4-hydroxybut-1-yn-1-yl)nicotinamide Example 194N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(phenylethynyl)nicotinamide Example 195N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-methylphenyl)ethynyl]nicotinamide Example 196N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(3-methoxyprop-1-yn-1-yl)nicotinamide Example 197N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(3,3-dimethylbut-1-yn-1-yl)nicotinamide Example 198N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-nitrophenyl)ethynyl]nicotinamide Example 199N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-prop-1-yn-1-ylnicotinamide Example 200N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(pyridin-2-ylethynyl)nicotinamide Example 201N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3-hydroxyphenyl)ethynyl]nicotinamide Example 202N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(6-methoxy-2-naphthyl)ethynyl]nicotinamide Example 203N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3-methoxyphenyl)ethynyl]nicotinamide Example 204N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-methoxyphenyl)ethynyl]nicotinamide Example 2055-[(4-bromophenyl)ethynyl]-N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 206N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[3-(4,5-dichloro-1H-imidazol-1-yl)prop-1-yn-1-yl]nicotinamide Example 2075-[(4-chlorophenyl)ethynyl]-N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 2085-[(2-chlorophenyl)ethynyl]-N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 209N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3-methylphenyl)ethynyl]nicotinamide Example 210N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-{[4-(trifluoromethyl)phenyl]ethynyl}nicotinamide Example 2115-[(2-bromophenyl)ethynyl]-N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 212N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(2,4-difluorophenyl)ethynyl]nicotinamide Example 213N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(1-naphthylethynyl)nicotinamide Example 214N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(pyridin-3-ylethynyl)nicotinamide Example 215N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3-fluorophenyl)ethynyl]nicotinamide Example 216N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(2-methylphenyl)ethynyl]nicotinamide Example 2175-[(3-bromophenyl)ethynyl]-N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 2185-[(3-chlorophenyl)ethynyl]-N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 219N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3,5-dimethoxyphenyl)ethynyl]nicotinamide Example 220N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3,4-dimethoxyphenyl)ethynyl]nicotinamide Example 221N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(2-methoxyphenyl)ethynyl]nicotinamide Example 222N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-piperidin-1-ylphenyl)ethynyl]nicotinamide Example 223N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3,5-difluorophenyl)ethynyl]nicotinamide Example 224N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(1-methyl-1H-imidazol-5-yl)ethynyl]nicotinamide Example 225N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-methoxy-2-methylphenyl)ethynyl]nicotinamide Example 226N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-fluoro-3-methylphenyl)ethynyl]nicotinamide Example 227N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(4-hydroxybut-1-yn-1-yl)nicotinamide Example 228N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(phenylethynyl)nicotinamide Example 229N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-methylphenyl)ethynyl]nicotinamide Example 230N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(3-methoxyprop-1-yn-1-yl)nicotinamide Example 231N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(3,3-dimethylbut-1-yn-1-yl)nicotinamide Example 232N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-prop-1-yn-1-ylnicotinamide Example 233N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(pyridin-2-ylethynyl)nicotinamide Example 234N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3-hydroxyphenyl)ethynyl]nicotinamide Example 235N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(6-methoxy-2-naphthyl)ethynyl]nicotinamide Example 236N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3-methoxyphenyl)ethynyl]nicotinamide Example 237N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-methoxyphenyl)ethynyl]nicotinamide Example 2385-[(4-bromophenyl)ethynyl]-N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 2395-[(4-chlorophenyl)ethynyl]-N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 2405-[(2-chlorophenyl)ethynyl]-N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 241N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3-methylphenyl)ethynyl]nicotinamide Example 242N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-{[4-(trifluoromethyl)phenyl]ethynyl}nicotinamide Example 2435-[(2-bromophenyl)ethynyl]-N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 244N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(2,4-difluorophenyl)ethynyl]nicotinamide Example 245N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(1-naphthylethynyl)nicotinamide Example 246N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3-fluorophenyl)ethynyl]nicotinamide Example 247N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(2-methylphenyl)ethynyl]nicotinamide Example 2485-[(3-bromophenyl)ethynyl]-N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 2495-[(3-chlorophenyl)ethynyl]-N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 250N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3,5-dimethoxyphenyl)ethynyl]nicotinamide Example 251N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3,4-dimethoxyphenyl)ethynyl]nicotinamide Example 252N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(2-methoxyphenyl)ethynyl]nicotinamide Example 253N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3,5-difluorophenyl)ethynyl]nicotinamide Example 254N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(1-methyl-1H-imidazol-5-yl)ethynyl]nicotinamide Example 255N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-methoxy-2-methylphenyl)ethynyl]nicotinamide Example 256N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-fluoro-3-methylphenyl)ethynyl]nicotinamide Example 2575-(4-hydroxybut-1-yn-1-yl)-N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 258N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]-5-(phenylethynyl)nicotinamide Example 259N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]-5-[(4-methylphenyl)ethynyl]nicotinamide Example 2605-(3-methoxyprop-1-yn-1-yl)-N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 2615-(3,3-dimethylbut-1-yn-1-yl)-N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 262N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]-5-[(4-nitrophenyl)ethynyl]nicotinamide Example 263N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]-5-prop-1-yn-1-ylnicotinamide Example 264N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]-5-(pyridin-2-ylethynyl)nicotinamide Example 2655-[(3-hydroxyphenyl)ethynyl]-N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 2665-[(6-methoxy-2-naphthyl)ethynyl]-N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 2675-[(3-methoxyphenyl)ethynyl]-N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 2685-[(4-methoxyphenyl)ethynyl]-N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 2695-[(4-bromophenyl)ethynyl]-N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 2705-[3-(4,5-dichloro-1H-imidazol-1-yl)prop-1-yn-1-yl]-N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 2715-[(4-chlorophenyl)ethynyl]-N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 2725-[(2-chlorophenyl)ethynyl]-N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 273N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]-5-[(3-methylphenyl)ethynyl]nicotinamide Example 274N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]-5-{[4-(trifluoromethyl)phenyl]ethynyl}nicotinamide Example 2755-[(2-bromophenyl)ethynyl]-N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 2765-[(2,4-difluorophenyl)ethynyl]-N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 277N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]-5-(1-naphthylethynyl)nicotinamide Example 278N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]-5-(pyridin-3-ylethynyl)nicotinamide Example 2795-[(3-fluorophenyl)ethynyl]-N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 280N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]-5-(pyridin-4-ylethynyl)nicotinamide Example 281N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]-5-[(2-methylphenyl)ethynyl]nicotinamide Example 2825-[(3-bromophenyl)ethynyl]-N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 2835-[(3-chlorophenyl)ethynyl]-N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 2845-[(3,5-dimethoxyphenyl)ethynyl]-N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 2855-[(3,4-dimethoxyphenyl)ethynyl]-N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 2865-[(2-methoxyphenyl)ethynyl]-N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 287N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]-5-[(4-piperidin-1-ylphenyl)ethynyl]nicotinamide Example 2885-[(3,5-difluorophenyl)ethynyl]-N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 2895-[(1-methyl-1H-imidazol-5-yl)ethynyl]-N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 2905-[(4-methoxy-2-methylphenyl)ethynyl]-N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 2915-[(4-fluoro-3-methylphenyl)ethynyl]-N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 2925-(4-hydroxybut-1-yn-1-yl)-N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 293N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(phenylethynyl)nicotinamide Example 294N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-methylphenyl)ethynyl]nicotinamide Example 295N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(3-methoxyprop-1-yn-1-yl)nicotinamide Example 2965-(3,3-dimethylbut-1-yn-1-yl)-N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 297N-[(3-methoxyphenyl)(methyl)oxo-λ6-sulfanylidene]-5-prop-1-yn-1-ylnicotinamide Example 298N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(pyridin-2-ylethynyl)nicotinamide Example 2995-[(3-hydroxyphenyl)ethynyl]-N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 3005-[(6-methoxy-2-naphthyl)ethynyl]-N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 3015-[(3-methoxyphenyl)ethynyl]-N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 3025-[(4-methoxyphenyl)ethynyl]-N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 3035-[(4-bromophenyl)ethynyl]-N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 3045-[3-(4,5-dichloro-1H-imidazol-1-yl)prop-1-yn-1-yl]-N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 3055-[(4-chlorophenyl)ethynyl]-N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 3065-[(2-chlorophenyl)ethynyl]-N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 307N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3-methylphenyl)ethynyl]nicotinamide Example 308N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-{[4-(trifluoromethyl)phenyl]ethynyl}nicotinamide Example 3095-[(2-bromophenyl)ethynyl]-N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 3105-[(2,4-difluorophenyl)ethynyl]-N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 311N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(1-naphthylethynyl)nicotinamide Example 312N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(pyridin-3-ylethynyl)nicotinamide Example 3135-[(3-fluorophenyl)ethynyl]-N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 314N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(pyridin-4-ylethynyl)nicotinamide Example 315N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(2-methylphenyl)ethynyl]nicotinamide Example 3165-[(3-bromophenyl)ethynyl]-N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 3175-[(3-chlorophenyl)ethynyl]-N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 3185-[(3,5-dimethoxyphenyl)ethynyl]-N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 3195-[(3,4-dimethoxyphenyl)ethynyl]-N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 3205-[(2-methoxyphenyl)ethynyl]-N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 3215-[(3,5-difluorophenyl)ethynyl]-N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 322N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(1-methyl-1H-imidazol-5-yl)ethynyl]nicotinamide Example 3235-[(4-methoxy-2-methylphenyl)ethynyl]-N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 3245-[(4-fluoro-3-methylphenyl)ethynyl]-N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 325N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(4-hydroxybut-1-yn-1-yl)nicotinamide Example 326N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(phenylethynyl)nicotinamide Example 327N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-methylphenyl)ethynyl]nicotinamide Example 328N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(3-methoxyprop-1-yn-1-yl)nicotinamide Example 3295-(3,3-dimethylbut-1-yn-1-yl)-N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 330N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-nitrophenyl)ethynyl]nicotinamide Example 331N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-prop-1-yn-1-ylnicotinamide Example 332N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(pyridin-2-ylethynyl)nicotinamide Example 333N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3-hydroxyphenyl)ethynyl]nicotinamide Example 334N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(6-methoxy-2-naphthyl)ethynyl]nicotinamide Example 335N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3-methoxyphenyl)ethynyl]nicotinamide Example 336N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-methoxyphenyl)ethynyl]nicotinamide Example 3375-[(4-bromophenyl)ethynyl]-N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 3385-[3-(4,5-dichloro-1H-imidazol-1-yl)prop-1-yn-1-yl]-N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 3395-[(4-chlorophenyl)ethynyl]-N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 3405-[(2-chlorophenyl)ethynyl]-N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 341N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3-methylphenyl)ethynyl]nicotinamide Example 342N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-{[4-(trifluoromethyl)phenyl]ethynyl}nicotinamide Example 3435-[(2-bromophenyl)ethynyl]-N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 3445-[(2,4-difluorophenyl)ethynyl]-N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 345N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(1-naphthylethynyl)nicotinamide Example 346N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(pyridin-3-ylethynyl)nicotinamide Example 347N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3-fluorophenyl)ethynyl]nicotinamide Example 348N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(pyridin-4-ylethynyl)nicotinamide Example 349N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(2-methylphenyl)ethynyl]nicotinamide Example 3505-[(3-bromophenyl)ethynyl]-N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 3515-[(3-chlorophenyl)ethynyl]-N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 3525-[(3,4-dimethoxyphenyl)ethynyl]-N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 353N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(2-methoxyphenyl)ethynyl]nicotinamide Example 3545-[(3,5-difluorophenyl)ethynyl]-N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 355N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(1-methyl-1H-imidazol-5-yl)ethynyl]nicotinamide Example 356N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-methoxy-2-methylphenyl)ethynyl]nicotinamide Example 357N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-fluoro-3-methylphenyl)ethynyl]nicotinamide Example 358N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(4-hydroxybut-1-yn-1-yl)nicotinamide Example 359N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(phenylethynyl)nicotinamide Example 360N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-methylphenyl)ethynyl]nicotinamide Example 361N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(3-methoxyprop-1-yn-1-yl)nicotinamide Example 3625-(3,3-dimethylbut-1-yn-1-yl)-N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 363N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-nitrophenyl)ethynyl]nicotinamide Example 364N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-prop-1-yn-1-ylnicotinamide Example 365N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(pyridin-2-ylethynyl)nicotinamide Example 366N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(6-methoxy-2-naphthyl)ethynyl]nicotinamide Example 367N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3-methoxyphenyl)ethynyl]nicotinamide Example 368N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-methoxyphenyl)ethynyl]nicotinamide Example 3695-[(4-bromophenyl)ethynyl]-N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 3705-[3-(4,5-dichloro-1H-imidazol-1-yl)prop-1-yn-1-yl]-N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 3715-[(4-chlorophenyl)ethynyl]-N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 3725-[(2-chlorophenyl)ethynyl]-N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 373N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3-methylphenyl)ethynyl]nicotinamide Example 374N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-{[4-(trifluoromethyl)phenyl]ethynyl}nicotinamide Example 3755-[(2-bromophenyl)ethynyl]-N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 3765-[(2,4-difluorophenyl)ethynyl]-N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 377N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(1-naphthylethynyl)nicotinamide Example 378N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(pyridin-3-ylethynyl)nicotinamide Example 379N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3-fluorophenyl)ethynyl]nicotinamide Example 380N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(pyridin-4-ylethynyl)nicotinamide Example 381N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(2-methylphenyl)ethynyl]nicotinamide Example 3825-[(3-bromophenyl)ethynyl]-N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 3835-[(3-chlorophenyl)ethynyl]-N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 3845-[(3,5-dimethoxyphenyl)ethynyl]-N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 3855-[(3,4-dimethoxyphenyl)ethynyl]-N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 386N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(2-methoxyphenyl)ethynyl]nicotinamide Example 387N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-piperidin-1-ylphenyl)ethynyl]nicotinamide Example 3885-[(3,5-difluorophenyl)ethynyl]-N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 389N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(1-methyl-1H-imidazol-5-yl)ethynyl]nicotinamide Example 390N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-methoxy-2-methylphenyl)ethynyl]nicotinamide Example 391N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-fluoro-3-methylphenyl)ethynyl]nicotinamide Example 392N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(4-hydroxybut-1-yn-1-yl)nicotinamide Example 393N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(phenylethynyl)nicotinamide Example 394N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-methylphenyl)ethynyl]nicotinamide Example 395N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(3-methoxyprop-1-yn-1-yl)nicotinamide Example 396N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(3,3-dimethylbut-1-yn-1-yl)nicotinamide Example 397N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-nitrophenyl)ethynyl]nicotinamide Example 398N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-prop-1-yn-1-ylnicotinamide Example 399N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(pyridin-2-ylethynyl)nicotinamide Example 400N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3-hydroxyphenyl)ethynyl]nicotinamide Example 401N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(6-methoxy-2-naphthyl)ethynyl]nicotinamide Example 402N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3-methoxyphenyl)ethynyl]nicotinamide Example 403N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-methoxyphenyl)ethynyl]nicotinamide Example 4045-[(4-bromophenyl)ethynyl]-N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 4055-[(4-chlorophenyl)ethynyl]-N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 4065-[(2-chlorophenyl)ethynyl]-N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 407N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3-methylphenyl)ethynyl]nicotinamide Example 408N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-{[4-(trifluoromethyl)phenyl]ethynyl}nicotinamide Example 4095-[(2-bromophenyl)ethynyl]-N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 4105-[(2,4-difluorophenyl)ethynyl]-N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 411N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(1-naphthylethynyl)nicotinamide Example 412N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(pyridin-3-ylethynyl)nicotinamide Example 413N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ6-sulfanylidene]-5-[(3-fluorophenyl)ethynyl]nicotinamide Example 414N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(pyridin-4-ylethynyl)nicotinamide Example 415N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(2-methylphenyl)ethynyl]nicotinamide Example 4165-[(3-bromophenyl)ethynyl]-N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 4175-[(3-chlorophenyl)ethynyl]-N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 4185-[(3,5-dimethoxyphenyl)ethynyl]-N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 4195-[(3,4-dimethoxyphenyl)ethynyl]-N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide Example 420N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-piperidin-1-ylphenyl)ethynyl]nicotinamide Example 421N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-methoxy-2-methylphenyl)ethynyl]nicotinamide Example 422N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(4-fluoro-3-methylphenyl)ethynyl]nicotinamide

EXAMPLE 423(S)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-(phenylethynyl)nicotinamide

To a slurry of 5-(2-phenyleth-1-ynyl)nicotinic acid (339 mg, 1.5 mmol)in 6.0 mL THF at room temperature was added 1,1′-carbonyldiimidazole(271 mg, 1.7 mmol). After stirring 1.25 hour, a solution of(S)-(+)-S-methyl-5-phenylsulfoximine (260 mg, 1.7 mmol) in 1.5 mL THFwas added and the mixture heated at 50° C. for 22 hours. Then anadditional 50 mg (0.32 mmol) (S)-(+)-S-methyl-S-phenylsulfoximine wasadded and heating continued at 60° C. for 3.5 hours. The reaction wasquenched with NaHCO₃ solution and then extracted into EtOAc. The EtOAclayer was washed with NaHCO₃ solution, H₂O, brine, dried with anhydrousNa₂SO₄ and concentrated. The yellow oil obtained was chromatographedeluting with hexane/EtOAc to giveN-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-(phenylethynyl)nicotinamide asa white foam (303 mg, 55%).

EXAMPLE 424(R)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-(phenylethynyl)nicotinamide

In a manner similar to that described in Example 423,5-(2-phenyleth-1-ynyl)nicotinic acid and(R)-(−)-S-methyl-5-phenylsulfoximine were reacted to give the titlecompound as a white foam (54 mg, 25%).

EXAMPLE 4255-[(2-fluorophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamideStep 1 (S)-5-bromo-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

To a solution of 5-bromonicotinic acid (1.21 g, 6.0 mmol),N,N-diisopropylethylamine (2.1 mL, 12.0 mmol), and(S)-(+)-S-methyl-5-phenylsulfoximine (931 mg, 6.0 mmol) in DMF (11.0 mL)cooled to 0° C. was treated with1-benzotriazolyloxytripyrrolidinylphosphonium hexafluorophosphate(PyBOP) (3.43 g, 6.6 mmol). The reaction mixture was stirred 10 minutes,the ice bath removed, and the reaction continued at room temperature for2 hours. The mixture was taken up in EtOAc and washed with H₂O, Na₂CO₃solution, brine, AcOH solution, H₂O, Na₂CO₃ solution, brine, dried withanhydrous Na₂SO₄ and concentrated. The residual brown oil was purifiedby chromatography (silica gel, hexane/EtOAc). The product containingeluent was concentrated and then triturated with hexane to give thetitle compound as an off-white solid (1.88 g, 92%).

Step 2(S)-5-[(2-fluorophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

A mixture of(S)-5-bromo-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide (105 mg,0.31mmol) and 1-ethynyl-2-fluorobenzene (75 mg, 0.62 mmol) in 2.0 mLEtOAc was degassed with argon at 70° C. Upon cooling to room temperaturethe reaction mixture was treated with triethylamine (0.16 mL, 1.1 mmol),dichlorobis(triphenylphosphine)palladium(II) (22 mg, 0.031 mmol) andcopper(I) iodide (2 mg, 0.012 mmol). The reaction was heated at 70° C.for 20 hours then partitioned between EtOAc and H₂O. The EtOAc layer waswashed with acetic acid solution, saturated NaHCO₃, brine, dried withanhydrous Na₂SO₄ and concentrated. The dark film obtained was purifiedby chromatography (silica gel, hexane/EtOAc) to give the title compoundas a tan foam (110 mg, 94%).

EXAMPLE 426(S)-5-[(4-chlorophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

In a manner similar to that describe in Example 425 a mixture of(S)-5-bromo-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide and4-chloro-1-ethynylbenzene were reacted to give the title compound aswhite needles (60 mg, 49%).

EXAMPLE 427(S)-5-[(3-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

In a manner similar to that describe in Example 425, a mixture of(S)-5-bromo-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide and3-hydroxy-1-ethynylbenzene were reacted to give the title compound as anoff-white solid (19 mg, 17%).

EXAMPLE 428(S)-5-[(4-phenoxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

In a manner similar to that describe in Example 425 a mixture of(S)-5-bromo-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide and1-ethynyl-4-phenoxybenzene were reacted to give the title compound as anoff-white solid (95 mg, 68%).

EXAMPLE 429(S)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide

To a degassed solution of 10.0 mL DMF at room temperature was added(S)-5-bromo-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide (1.02 g,3.0 mmol), triethylamine (1.3 mL, 9.0 mmol), trimethylsilylacetylene(0.83 mL, 6.0 mmol), and dichlorobis(triphenylphosphine)palladium(II)(211 mg, 0.3 mmol). After 15 minutes added copper(I) iodide (29 mg, 0.15mmol) and continued reaction for 4 hours. The reaction was thenpartitioned between EtOAc and H₂O. The EtOAc layer was washed withsaturated NaHCO₃, brine, dried with anhydrous Na₂SO₄ and rotaryevaporated to 20 ml volume. The solution was placed overnight in therefrigerator and the resulting solid filtered and rinsed with 40%EtOAc/hexane to give the title compound (674 mg) as a tan solid. Thefiltrate was evaporated and purified by chromatography (silica gel,eluting with hexane/EtOAc) to give an additional 301 mg of the titlecompound. The product lots were combined and purified by chromatography(silica gel, eluting with hexane/EtOAc) to give the title compound as atan solid (959 mg, 90%).

EXAMPLE 430(S)-5-ethynyl-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

A solution of(S)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide(806 mg, 2.3 mmol) in 70 mL THF/methanol (1:1 ratio) at room temperaturewas degassed with argon. The solution was cooled to 0° C. and K₂CO₃ (937mg, 6.8 mmol) added. After 5 minutes the solution was decanted from thesolids and partitioned between EtOAc and H₂O. The EtOAc layer was washedwith brine, dried with anhydrous Na₂SO₄ and concentrated. The brown oilwas purified by chromatography (silica gel, CHCl₃/EtOAc) to the titlecompound as a thick pale orange oil (630 mg, 98%).

EXAMPLE 431(S)-5-[(4-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

To a degassed solution of 1.3 mL DMF at room temperature containing(S)-5-ethynyl-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide (63 mg,0.22 mmol), 4-iodophenol (121 mg, 0.55 mmol), and triethylamine (0.09mL, 0.66 mmol) was added dichlorobis(triphenylphosphine)palladium(II)(15 mg, 0.022 mmol) and copper(I) iodide (4 mg, 0.022 mmol). Afterproceeding for 1 hour the reaction was partitioned between EtOAc andH₂O. The mixture was filtered to remove an insoluble brown precipitateand the EtOAc layer was washed with H₂O, brine, dried with anhydrousNa₂SO₄ and rotary evaporated. The brown film was chromatographed elutingwith CHCl₃/EtOAc to give a yellow solid which was recrystallized fromCHCl₃/hexane to give the title compound as an off-white solid (38 mg,45%).

EXAMPLE 432(S)-5-[(2-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

In a manner similar to that describe in Example 431 a mixture of(S)-5-ethynyl-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide and1-ethynyl-2-hydroxybenzene were reacted to give the title compound as awhite solid (6 mg, 7%).

EXAMPLE 433 Step 1(R)-5-bromo-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

To a solution of 5-bromonicotinic acid (303 mg, 1.5 mmol),N,N-diisopropylethylamine (0.523 mL, 3.0 mmol), and(R)-(−)-S-methyl-5-phenylsulfoximine (233 mg, 1.5 mmol) in DMF (3.0 mL)cooled to 0° C. was added 1-benzotriazolyloxytripyrrolidinylphosphoniumhexafluorophosphate (PyBOP) (859 mg, 1.65 mmol). The solution wasstirred 10 minutes, the ice bath removed, and the reaction continued atroom temperature for 2.5 hours. The mixture was taken up in EtOAc andwashed with H₂O, Na₂CO₃ solution, brine, AcOH solution, H₂O, Na₂CO₃solution, brine, dried with anhydrous Na₂SO₄ and rotary evaporated. Thebrown oil was chromatographed eluting with hexane/EtOAc to give thetitle compound as a yellow solid (478 mg, 94%).

Step 2(R)-5-[(3-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

To a degassed solution of 2.0 mL DMF at room temperature containing(R)-5-bromo-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide (105 mg,0.31 mmol), 3-hydroxyphenylacetylene (73 mg, 0.62 mmol) andtriethylamine (0.13 mL, 0.93 mmol) was addeddichlorobis(triphenylphosphine)palladium(II) (22 mg, 0.031 mmol) andcopper(I) iodide (3 mg, 0.016 mmol). The reaction was stirred at roomtemperature for 1.5 hours. Additional 3-hydroxyphenylacetylene was added(30 mg, 0.25 mmol) and the reaction was stirred at room temperature foran additional 3.5 hours. After proceeding for 5 hours the reaction waspartitioned between EtOAc and H₂O and the EtOAc layer washed with H₂O,brine, dried with anhydrous Na₂SO₄ and concentrated. The residual darkoil was purified by chromatography (silica gel, CHCl₃/EtOAc) and theproduct containing fractions were concentrated. The resulting solid wastriturated with EtOAc/hexane to give the title compound as an off-whitesolid (37 mg, 32%).

EXAMPLE 434(S)-3-{[5-({[methyl(oxo)phenyl-λ⁶-sulfanylidene]amino}carbonyl)pyridin-3-yl]ethynyl}benzoicacid

A mixture of(S)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide(54 mg, 0.15 mmol), 3-iodobenzoic acid (56 mg, 0.23 mmol),dichlorobis(triphenylphosphine)palladium(II) (11 mg, 0.02 mmol),triphenylphosphine (1.0 mg, 0.004 mmol) and triethylamine (0.073 mL,0.53 mmol) in 1.5 mL DMF at room temperature was degassed using vacuumand a H₂/N₂ (1:1) mixture and then copper(I) iodide (2 mg, 0.01 mmol)added. The reaction was heated to 60° C. then tetrabutylammoniumfluoride (1.0 M in THF, 0.15 ml) added over 3.5 minutes. After 25minutes the reaction was partitioned between EtOAc and dilute AcOH. TheEtOAc layer was collected and washed with H₂O, brine, dried withanhydrous Na₂SO₄ and concentrated to a yellow solid. The solid wastriturated with EtOAc at room temperature to give the title compound asa yellow solid (45 mg, 74%).

EXAMPLE 435(S)-5-[(4-acetylphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

In a manner similar to that describe in Example 434 a mixture of(S)-5-ethynyl-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide and4-iodoacetophenone were reacted to give the title compound as a lightyellow foam (52 mg, 86%).

EXAMPLE 436(S)-5-[(4-hydroxy-3-methylphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

In a manner similar to that describe in Example 434, a mixture of(S)-5-ethynyl-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide and4-iodo-2-methylphenol were reacted to give the title compound as a lightyellow solid (43 mg, 73%).

EXAMPLE 437(S)-2-hydroxy-5-{[5-({[methyl(oxo)phenyl-λ⁶-sulfanylidene]amino}carbonyl)pyridin-3-yl]ethynyl}benzoicacid

In a manner similar to that describe in Example 434, a mixture of(S)-5-ethynyl-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide and5-iodosalicyclic acid were reacted to give the title compound as a lighttan solid (28 mg, 45%).

EXAMPLE 438(S)-4-{[5-({[methyl(oxo)phenyl-λ⁶-sulfanylidene]amino}carbonyl)pyridin-3-yl]ethynyl}benzoicacid

In a manner similar to that describe in Example 434, a mixture of(S)-5-ethynyl-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide and4-iodobenzoic acid were reacted to give the title compound as a lightyellow solid (30 mg, 49%).

EXAMPLE 439(S)-5-(1H-imidazol-5-ylethynyl)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

In a manner similar to that describe in Example 434, a mixture of(S)-5-ethynyl-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide and5-iodo-1H-imidazole were reacted to give the title compound as a whitefoam (24 mg, 46%).

EXAMPLE 440(S)-5-(1H-imidazol-2-ylethynyl)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

In a manner similar to that describe in Example 434, a mixture of(S)-5-ethynyl-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide and2-iodo-1H-imidazole were reacted to give the title compound as a whitesolid (15 mg, 29%).

EXAMPLE 441(S)-5-[(2-methyl-1H-imidazol-5-yl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

In a manner similar to that describe in Example 434, a mixture of(S)-5-ethynyl-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide and5-iodo-2-methyl-1H-imidazole were reacted to give the title compound asan off-white foam (28 mg, 51%).

EXAMPLE 442(S)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-(1H-pyrazol-4-ylethynyl)nicotinamide

In a manner similar to that describe in Example 431 a mixture of(S)-5-ethynyl-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide and4-iodopyrazole were reacted to give the title compound as a white film(15 mg, 17%).

EXAMPLE 443(S)-5-[(6-hydroxypyridin-3-yl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

A solution of(S)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-[(trimethylsilyl)ethynyl]-nicotinamide(150 mg, 0.42 mmol) and 2-hydroxy-5-iodopyridine (105.4 mg, 0.46 mmol)in DMF (2.1 mL) was degassed (vacuum and argon). The resulting solutionwas treated tetrakis(triphenylphosphine)palladium(0) (24 mg, 0.021mmol), triethylamine (0.08 mL, 0.55 mmol), and CuI (8 mg, 0.042 mmol).The reaction mixture was then heated to 85° C. and tetrabutylammoniumfluoride (1.0 M solution in THF, 0.46 mL, 0.46 mmol) was added dropwiseover 10 min. The reaction was allowed to be stirred at 85° C. for 2hours. The reaction mixture was partitioned between EtOAc and H₂O. Theorganic extracts and associated solid were collected and concentrated.The residue was purified by chromatography (silica gel, gradient elutionMeOH—CHCl₃: 1:100-1:4). The product containing fractions were collected,concentrated, and the brown solid residue was triturated with acombination of MeOH and EtOAc. The resulting mixture was filtered andthe filtrate allowed to stand at room temperature. The solid whichprecipitated from solution was collected and dried to give the titlecompound as a white solid (11 mg).

EXAMPLE 444(S)-5-(1H-indol-6-ylethynyl)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

In a manner similar to that described in Example 443,(S)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide(150 mg, 0.42 mmol) and 6-bromoindole (90.7 mg, 0.46 mmol) were reactedto give the title compound (30 mg).

EXAMPLE 445(S)-5-[(2,3-dioxo-2,3-dihydro-1H-indol-5-yl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

In a manner similar to that described in Example 443,(S)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide(150 mg, 0.42 mmol) and 5-bromoisatin (116 mg, 0.46 mmol) were reactedto give the title compound as a reddish oil (40 mg).

EXAMPLE 446(S)-5-[(6-chloropyridin-3-yl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

In a manner similar to that described in Example 443,(S)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide(250 mg, 0.70 mmol) and 2-chloro-5-iodopyridine (173 mg, 0.70 mmol) werereacted to give the title compound as white solid (250 mg).

EXAMPLE 447(S)-5-[(6-aminopyridin-3-yl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

In a manner similar to that described in Example 443,(S)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide(100 mg, 0.28 mmol) and 2-amino-5-iodopyridine (69.3 mg, 0.31 mmol) werereacted to give the title compound as light yellow solid (89 mg).

EXAMPLE 448(S)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-[(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)ethynyl]nicotinamide

In a manner similar to that described in Example 443,(S)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide(150 mg, 0.42 mmol) and 5-bromo-2-benzoxazolinone (102 mg, 0.46 mmol)were reacted to give the title compound as light yellow solid (71 mg).

EXAMPLE 449(S)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-({4-[(2-thienylcarbonyl)amino]phenyl}ethynyl)nicotinamide

In a 4 mL vial, thiophene-2-carboxylic acid (4-ethynyl-phenyl)-amide(0.100 g, 0.443 mmol) and(S)-5-bromo-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide (100 mg,0.295 mmol) were added and dissolved into EtOAc (2 mL). The mixture wasthen degassed for ˜20 min after which NEt₃ (0.141 mL, 1.035 mmol) wasadded followed by Pd(PPh₃)₂Cl₂ (20.7 mg, 0.0295 mmol) and CuI (2.8 mg,0.148 mmol). The reaction mixture was allowed to stir at 50° C. for 3hours after which the reaction mixture was extracted twice with EtOAc(˜5 mL) and of water (˜5 mL). The organic extracts were combined anddried over anhydrous Na₂SO₄(s) and then concentrated in vacuo. The cruderesidue was then purified by chromatography (silica gel, gradientelution, 25% EtOAc/hexanes to 100% EtOAc/hexanes). The productcontaining fractions were concentrated to give the title compound as atan solid (87 mg, 0.18 mmol, 61%).

EXAMPLE 450(S)-5-{[3-(acetylamino)phenyl]ethynyl}-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

In a manner similar to that described in Example 449,N-(3-ethynyl-phenyl)-acetamide (0.0469 g, 0.443 mmol) and(S)-5-bromo-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide (100 mg,0.295 mmol) were reacted to give the title compound as a solid (83 mg,0.20 mmol, 67%).

EXAMPLE 451(S)-5-({4-[(2,6-difluorobenzoyl)amino]phenyl}ethynyl)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

In a manner similar to that described in Example 449,N-(4-ethynyl-phenyl)-2,6-difluoro-benzamide (0.114 g, 0.443 mmol) and(S)-5-bromo-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide (100 mg,0.295 mmol) were reacted to give the title compound as a solid (113 mg,74%)

EXAMPLE 452(S)-5-({4-[(4-fluorobenzoyl)amino]phenyl}ethynyl)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

In a manner similar to that described in Example 449,N-(4-ethynyl-phenyl)-4-fluoro-benzamide (0.106 g, 0.443 mmol) and5-bromo-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide (100 mg,0.295 mmol) were reacted to give the title compound as a solid (106 mg,72%).

EXAMPLE 453(S)-5-({4-[(4-methylbenzoyl)amino]phenyl}ethynyl)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

In a manner similar to that described in Example 449,N-(4-ethynyl-phenyl)-4-methyl-benzamide (0.104 g, 0.443 mmol) and(S)-5-bromo-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide (100 mg,0.295 mmol) were reacted to give the title compound as a solid (118 mg,81%).

EXAMPLE 454(S)-5-({4-[(2-methylbenzoyl)amino]phenyl}ethynyl)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

In a manner similar to that described in Example 449,N-(4-ethynyl-phenyl)-2-methyl-benzamide (0.104 g, 0.443 mmol) and(S)-5-bromo-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide (100 mg,0.295 mmol) were reacted to give the title compound (109 mg, 75%).

EXAMPLE 455 tert-butyl(4-{[5-({[methyl(oxo)phenyl-λ⁶-sulfanylidene]amino}carbonyl)pyridin-3-yl]ethynyl}phenyl)carbamateStep 1 tert-butyl 4-ethynylphenylcarbamate

A dry 25 mL flask was charged with 3-ethynyl-phenylamine (0.100 g, 0.855mmol) and then THF (5 mL) was added. Di-tert-butyl dicarbonate (0.242 g,1.11 mmol) was added to the THF solution followed by NEt₃ (0.231 mL,1.71 mL). The mixture was allowed to stir at 55° C. after which it wascooled to room temperature and extracted twice with EtOAc (˜10 mL),water (˜10 mL) and saturated aqueous NaHCO₃. The combined organicextracts were dried over anhydrous Na₂SO₄(s) and then concentrated togive the title compound (0.15 g, 0.67 mmol, 78%).

Step 2 (S)-tert-butyl(4-{[5-({[methyl(oxo)phenyl-λ⁶-sulfanylidene]amino}carbonyl)pyridin-3-yl]ethynyl}phenyl)carbamate

In a manner similar to that described in Example 449, tert-butyl4-ethynylphenylcarbamate (0.096 g, 0.443 mmol) and5-bromo-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide (100 mg,0.295 mmol) were reacted to give the title compound as a solid (63 mg,0.13 mmol, 45%).

EXAMPLE 456(S)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-({3-[(2-thienylcarbonyl)amino]phenyl}ethynyl)nicotinamideStep 1 N-(3-ethynylphenyl)thiophene-2-carboxamide

A dry 25 mL flask was charged with thiophene-2-carbonyl chloride and THF(5 mL) was added. 3-Ethynyl-phenylamine (0.905 g, 3.59 mmol) was addedto the THF solution of the acid chloride followed by NEt₃, and themixture was allowed to stir at 55° C. The reaction mixture was thenallowed to cool to room temperature and extracted with EtOAc (˜10 mL),1M HCl (˜10 mL), followed by brine (˜10 mL). The combined organicextracts were combined and dried over anhydrous Na₂SO₄(s) and theconcentrated. The crude residue was purified by chromatography (silicagel, gradient elution EtOAc/Hexanes 0 to 50%). The product containingfractions were concentrated to give the title compound as a tan solid(0.33 mg, 1.45 mmol, 85%).

Step 2(S)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-({3-[(2-thienylcarbonyl)amino]phenyl}ethynyl)nicotinamide

In a manner similar to that described in Example 449,thiophene-2-carboxylic acid (3-ethynyl-phenyl)-amide (0.100 g, 0.443mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide(100 mg, 0.295 mmol) were reacted to give the title compound as a solid(44 mg, 0.092 mmol, 31%).

EXAMPLE 457(S)-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamideStep 1 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid(3-ethynyl-phenyl)-amide

A dry 25 mL flask was charged with 2,5-dimethyl-2H-pyrazole-3-carbonylchloride (0.135 g, 0.854 mmol) and THF (5 mL) was added.3-Ethynyl-phenylamine (0.100 g, 0.854 mmol) was added to the THFsolution of the acid chloride followed by NEt₃, and the mixture wasallowed to stir at 55° C. The reaction mixture was then allowed to coolto room temperature. The reaction was extracted twice with EtOAc (5 mL)and water (10 mL) followed by saturated aqueous NaHCO₃ (˜10 mL). Thecombined organic layers were dried over anhydrous Na₂SO₄ (s) and thenconcentrated. The crude residue was purified by chromatography (silicagel, gradient elution EtOAc/Hexanes 0 to 60%). The product containingfractions were concentrated to give the title compound as a tan solid(147 mg. 72%).

Step 2(S)-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

In a manner similar to that described in Example 449,2,5-Dimethyl-2H-pyrazole-3-carboxylic acid (3-ethynyl-phenyl)-amide(0.0354 g, 0.222 mmol) and(S)-5-bromo-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide (0.050 g,0.148 mmol) were reacted to give the title compound as a white solid (47mg, 64%).

EXAMPLE 458N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-({3-[(3-methylthienyl-2-carbonyl)amino]phenyl}ethynyl)nicotinamideStep 1 N-(3-ethynylphenyl)-3-methylthiophene-2-carboxamide

A dry 25 mL flask was charged with 3-methylthiophene-2-carboxylic acid(0.201 g, 1.41 mmol) followed by thionyl chloride (10 mL). The reactionwas heated to 50° C. for 2 h after which the reaction was cooled to roomtemperature and concentrated to afford the crude acid chloride. Thecrude acid chloride was dissolved into 10 mL of THF and3-ethynyl-phenylamine (0.165 g, 1.41 mmol) was added to the solutionfollowed by NEt₃, and the mixture was allowed to stir at 55° C. for 4hours. The reaction mixture was allowed to cool to room temperature andthen partitioned between EtOAc and water. The organic layer was thenwashed once with of 1M HCl (˜10 mL) and then twice with of saturatedaqueousNaHCO₃ (˜10 mL). The organic extracts were combined, dried overanhydrous Na₂SO₄(s) and then concentrated to give the title compound asa tan solid (265 mg, 1.10 mmol, 78%).

Step 2(S)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-({3-[(3-methylthienyl-2-carbonyl)amino]phenyl}ethynyl)nicotinamide

In a manner similar to that described in Example 449,N-(3-ethynylphenyl)-3-methylthiophene-2-carboxamide (0.213 g, 0.885mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide(0.200 g, 0.590 mmol) were reacted to give the title compound as a solid(274 mg, 93%).

EXAMPLE 459 (S)-tert-butyl(3-{[5-({[methyl(oxo)phenyl-λ⁶-sulfanylidene]amino}carbonyl)pyridin-3-yl]ethynyl}phenyl)carbamateStep 1 tert-butyl 3-ethynylphenylcarbamate

A dry 25 mL flask was charged with 3-ethynyl-phenylamine (0.100 g, 0.855mmol) and THF (5 mL) was added. Di-tert-butyl dicarbonate (0.242 g, 1.11mmol) was added to the THF solution followed by NEt₃ (0.23 mL, 1.71mmol). The mixture was allowed to stir at 55° C. after which it wascooled to room temperature and extracted twice with EtOAc (˜10 mL),water (˜10 mL) and saturated aqueous NaHCO₃.

The combined organic extracts were dried over anhydrous Na₂SO₄(s) andthen concentrated to give the title compound (0.13 g, 0.67 mmol, 72%).

Step 2 (S)-tert-butyl(3-{[5-({[methyl(oxo)phenyl-λ⁶-sulfanylidene]amino}carbonyl)pyridin-3-yl]ethynyl}phenyl)carbamate

In a manner similar to that described in Example 449, tert-butyl3-ethynylphenylcarbamate (0.098 g, 0.443 mmol) and(S)-5-bromo-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide (0.100 g,0.295 mmol) reacted to give the title compounds as a white solid (32 mg,23%).

EXAMPLE 460(S)-5-({3-[(2-methylbenzoyl)amino]phenyl}ethynyl)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamideStep 1 N-(3-ethynylphenyl)-2-methylbenzamide

A dry 25 mL flask was charged with 2-methylbenzoyl chloride (0.155 g,1.00 mmol) was cooled to room temperature, and THF (10 mL) was added.3-Ethynyl-phenylamine (0.117 g, 1.00 mmol) was added to the THF solutionof the acid chloride followed by NEt₃ (0.272 mL, 2.00 mmol), and themixture was allowed to stir at 55° C. The reaction mixture was thenallowed to cool to room temperature and partitioned between EtOAc (10mL) and H₂O (15 mL). The organic layer was washed with then washed oncewith 1M HCl (20 mL) followed by of saturated aqueous NaHCO₃ (˜20 mL) andof brine (˜20 mL). The organic extracts were concentrated and the cruderesidue was purified by chromatography (silica gel, gradient elutionEtOAc/hexanes 10 to 70%). The product containing fractions wereconcentrated to give the title compound as a tan solid (434 mg, 0.88mmol, 88%).

Step 2(S)-5-({3-[(2-methylbenzoyl)amino]phenyl}ethynyl)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

In a 4 mL vial, N-(3-ethynylphenyl)-2-methylbenzamide (0.104 g, 0.443mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide(0.100 g, 0.295 mmol) were added and dissolved into EtOAc (2 mL) Themixture was then degassed for ˜20 min after which NEt₃ (0.141 mL, 1.035mmol) was added followed by Pd(PPh₃)₂Cl₂ (21.0 mg, 0.030 mmol) and CuI(2.9 mg, 0.016 mmol). The reaction mixture was allowed to stir at 50° C.for 4 hours after which the reaction mixture was partitioned betweenEtOAc (4 mL) and water (4 mL). The organic extracts were combined, driedover anhydrous Na₂SO₄ and concentrated. The residue as purified bychromatography (silica gel, gradient elution 25% EtOAc/Hexanes EtOAc).The product containing fractions were concentrated to give the titlecompound as a solid (121 mg, 83%).

EXAMPLE 461(S)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-({3-[(3-methylfuryl-2-carbonyl)amino]phenyl}ethynyl)nicotinamideStep 1 N-(3-ethynylphenyl)-3-methylfuran-2-carboxamide

A dry 25 mL flask was charged with 3-methylfuran-2-carboxylic acid(0.500 g, 3.46 mmol) and thionyl chloride (10 mL). The reaction washeated to 50° C. and allowed to react for 2 h. The reaction was thencooled to room temperature and concentrated affording the crude acidchloride. The acid chloride was then dissolved in THF (5 mL) and3-ethynyl-phenylamine (0.41 g, 3.47 mmol) was added followed by NEt₃(0.95 mL, 7 mmol). The mixture was allowed to stir at 55° C. for 3 hoursand the cooled to room temperature. The reaction was then partitionedbetween EtOAc and water. The organic layer was then washed once with 1MHCl (5 mL) and then once with saturated aqueous NaHCO₃ (5 mL). Theorganic extracts were then concentrated to give the title compound as alight brown solid (631 mg, 2.80 mmol, 81%).

Step 2(S)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-({3-[(3-methylfuryl-2-carbonyl)amino]phenyl}ethynyl)nicotinamide

In a manner similar to that described in Example 460,N-(3-ethynylphenyl)-3-methylfuran-2-carboxamide (0.199 g, 0.885 mmol)and (S)-5-bromo-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide(0.200 g, 0.590 mmol) were reacted to give the title compound as a solid(243 mg, 87%).

EXAMPLE 462 (S)-tert-butyl(5-{[5-({[methyl(oxo)phenyl-λ⁶-sulfanylidene]amino}carbonyl)pyridin-3-yl]ethynyl}-1,3-thiazol-2-yl)carbamateStep 1 tert-butyl (5-bromo-1,3-thiazol-2-yl)carbamate

The title compound was prepared by a modification of the proceduredescribed in J. Med. Chem. 2005, 48, 1886-1900. A mixture of2-amino-6-bromothiazole monohydrobromide (390 mg, 1.5 mmol) and NaHCO₃(441 mg, 5.3 mmol) in 6.0 mL tert-butyl alcohol was heated for 1 minuteat near reflux, then cooled to room temperature. To this mixture wasadded DMAP (18 mg, 0.15 mmol) and di-tert-butyl dicarbonate (1.0 M inTHF, 1.65 mL) and the reaction stirred at room temperature for 16 hours.In order to drive reaction to completion, additional di-tert-butyldicarbonate (1.0 M in THF, 0.5 mL) was added, the reaction heated at 50°C. for 2 hours, then di-tert-butyl dicarbonate (1.0 M in THF, 1.0 mL)and 100 mg NaHCO₃ added and continued heating at 50° C. an additional 2hours. The mixture was filtered and rinsed with EtOAc, then the EtOAcfiltrate washed with H₂O, dilute aqueous HCl, saturated NaHCO₃ solution,brine, dried with anhydrous anhydrous Na₂SO₄ and rotary evaporated. Thebrown solid was chromatographed eluting with hexane/EtOAc and theproduct triturated with hexane to give the title compound as a creamsolid (204 mg, 49%).

Step 2 (S)-tert-butyl(5-{[5-({[methyl(oxo)phenyl-λ⁶-sulfanylidene]amino}carbonyl)pyridin-3-yl]ethynyl}-1,3-thiazol-2-yl)carbamate

A mixture ofN-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide(73 mg, 0.21 mmol), tert-butyl (5-bromo-1,3-thiazol-2-yl)carbamate (74mg, 0.27 mmol), dichlorobis(triphenylphosphine)palladium(II) (14 mg,0.02 mmol), triphenylphosphine (2.7 mg, 0.004 mmol) and triethylamine(0.071 mL, 0.51 mmol) in 1.8 mL DMF at room temperature was degassedusing vacuum and a H₂/N₂ (1:1) mixture and then copper(I) iodide (2 mg,0.01 mmol) added. While stirring the mixture at room temperature,tetrabutylammonium fluoride (1.0 M in THF, 0.21 mL) was added over 2.5minutes. After 5 minutes the reaction was heated at 60° C. for 2 hours.The reaction was partitioned between EtOAc and H₂O and the EtOAc layerwashed with H₂O, aqueous HCl, saturated NaHCO₃ solution, brine, driedwith anhydrous Na₂SO₄ and concentrated. The brown oil waschromatographed eluting with hexane/acetone and the product containingfractions were concentrated to give the title compound as a light yellowsolid (17 mg, 18%).

EXAMPLE 463(S)-5-[(2-amino-1,3-thiazol-5-yl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

To a solution containing tert-butyl(5-{[5-({[methyl(oxo)phenyl-λ⁶-sulfanylidene]amino}carbonyl)pyridin-3-yl]ethynyl}-1,3-thiazol-2-yl)carbamate(16 mg, 0.032 mmol) in 2.0 mL dichloromethane at room temperature wasadded trifluoroacetic acid (0.099 mL, 1.3 mmol). The reaction wasstirred at room temperature for 17 hours, then partitioned between EtOAcand saturated NaHCO₃ solution. The EtOAc layer was washed with H₂O,brine, dried with anhydrous Na₂SO₄ and rotary evaporated. The resultingsolid film was purified by chromatography (silica gel, CHCl₃/EtOAc) togive the title compound as a tan solid (9 mg, 74%).

EXAMPLE 464(S)-5-{[2-(benzoylamino)-1,3-thiazol-5-yl]ethynyl}-N-[methyl(oxo)phenyl-lambda˜4˜-sulfanylidene]nicotinamide

Step 1 N-(5-bromo-1,3-thiazol-2-yl)benzamide

A mixture of 2-amino-6-bromothiazole monohydrobromide (156 mg, 0.6 mmol)in 2.0 mL pyridine (degassed) at room temperature was added benzoylchloride (0.058 mL, 0.5 mmol) over 1 minute. After stirring at roomtemperature for 20 minutes the reaction was quenched with H₂O, and thenextracted into EtOAc. The EtOAc layer was washed with H₂O, saturatedNaHCO₃ solution, brine, dried with anhydrous Na₂SO₄ and rotaryevaporated. The solid was triturated with hot 10% EtOAc/hexane to give aquantitative yield (142 mg) of the title compound as a light tan solid.

Step 25-{[2-(benzoylamino)-1,3-thiazol-5-yl]ethynyl}-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

In a manner similar to that described in Example 462,5-ethynyl-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide (74 mg,0.26 mmol), N-(5-bromo-1,3-thiazol-2-yl)benzamide (74 mg, 0.26 mmol)were reacted to give the title compound as a cream solid (33 mg, 26%).

EXAMPLE 465(S)-6-amino-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamideStep 1 methyl 6-amino-5-iodonicotinate

To a solution of iodine (3.55 g, 14.0 mmol) in 100 mL absolute ethanolat room temperature was added silver sulfate (4.37 g, 14.0 mmol) andmethyl 6-aminonicotinate (1.52 g, 10.0 mmol). After 42 hours thereaction was filtered to isolate a tan precipitate. The solid was heatedwith 20% MeOH/CHCl₃ then cooled to room temperature, filtered, andrinsed with MeOH and CHCl₃. The filtrate was evaporated, dissolved inhot MeOH, filtered to remove brownish impurities, and then crystallizedfrom MeOH to give the title compound as a light tan solid (1.73 g, 62%).

Step 2 6-amino-5-iodonicotinic acid

A solution of methyl 6-amino-5-iodonicotinate (723 mg, 2.6 mmol) andpotassium hydroxide (729 mg, 13.0 mmol) in 40 mL methanol/H₂O (3:1ratio) was heated at 50° C. After 4 hours 10 mL THF was added and thereaction continued until 22 hours. The reaction was cooled to roomtemperature and concentrated HCl added until the solution was pH 4. Thesolution was concentrated to a volume of 15 mL and the resultingprecipitate filtered, rinsed with H₂O and 40% EtOAc/hexane to give thetitle compound as a white solid (443 mg, 65%).

Step 3(S)-6-amino-5-iodo-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

To a solution of 6-amino-5-iodonicotinic acid (330 mg, 1.3 mmol),N,N-diisopropylethylamine (0.44 mL, 2.5 mmol), and(S)-(+)-S-methyl-5-phenylsulfoximine (291 mg, 1.9 mmol) in 7.0 mL DMF atroom temperature was added BOP (608 mg, 1.4 mmol). The solution wasstirred 10 minutes and then heated at 60° C. for 5 hours. The mixturewas dissolved in EtOAc, washed with Na₂CO₃ solution, H₂O, brine, driedwith anhydrous Na₂SO₄ and rotary evaporated. The brown oil was purifiedby chromatography (silica gel, hexane/acetone). The product containingfractions were purified by chromatography one additional time (silicagel, EtOAc/MeOH). To give the title compound as a white foam (354 mg,71%).

Step 4(S)-6-amino-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide

To a degassed solution containing(S)-6-amino-5-iodo-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide(345 mg, 0.86 mmol) in 6.0 mL DMF at room temperature was addedtriethylamine (0.36 mL, 2.6 mmol), trimethylsilylacetylene (0.24 mL, 1.7mmol), dichlorobis(triphenylphosphine)palladium(II) (60 mg, 0.09 mmol),and copper(I) iodide (16 mg, 0.09 mmol). After stirring at roomtemperature for 1 hour, the reaction was partitioned between EtOAc andH₂O. The EtOAc layer was washed with saturated NaHCO₃, brine, dried withanhydrous Na₂SO₄ and rotary evaporated. Then added 30 mL ethyl ether tothe dark oil, filtered to remove the dark precipitate. The organicextracts were concentrated and the residue was purified bychromatography (silica gel, ethyl ether/EtOAc) to the title compound asa tan foam (317 mg, 99%).

EXAMPLE 466(S)-6-amino-5-ethynyl-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

To a solution of(S)-6-amino-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide(308 mg, 0.83 mmol) in 20 mL THF/methanol (1:1 ratio) at 0° C. was addedK₂CO₃ (344 mg, 2.5 mmol) added. After 7 minutes the solution wasdecanted from the solids and partitioned between EtOAc and H₂O. TheEtOAc layer was washed with brine, dried with anhydrous Na₂SO₄ androtary evaporated. The brown oil was purified by chromatography (silicagel, CHCl₃/EtOAc) to give the title compound as a white solid (193 mg,78%).

EXAMPLE 4676-amino-5-[(3-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

A mixture of(S)-6-amino-5-ethynyl-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide(60 mg, 0.2 mmol), 3-iodophenol (66 mg, 0.3 mmol), triethylamine (0.07mL, 0.5 mmol), dichlorobis(triphenylphosphine)palladium(II) (14 mg, 0.02mmol), triphenylphosphine (1.3 mg, 0.005 mmol) in 1.8 mL DMF at roomtemperature was degassed using a H₂/N₂ (1:1) mixture and then copper(I)iodide (2 mg, 0.01 mmol) added. The reaction was heated at 60° C. for 15minutes and then partitioned between EtOAc and saturated NaHCO₃. TheEtOAc layer was washed with brine, dried with anhydrous Na₂SO₄ androtary evaporated to a brown oil. Before chromatography a different lotof product (23 mg) was added and the combined lots were purified bychromatography (silica gel, EtOAc/EtOH) to the title compound as anoff-white solid (91 mg, 89%).

EXAMPLE 468(S)-6-amino-5-[(4-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

In a manner similar to that describe in Example 467,(S)-6-amino-5-ethynyl-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamideand 4-iodophenol are converted to the title compound (41 mg, 62%).

EXAMPLE 469(S)-2-amino-5-[(3-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamideStep 1(S)-2-amino-5-bromo-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

To a solution of 2-amino-5-bromonicotinic acid (189 mg, 0.87 mmol),N,N-diisopropylethylamine (0.30 mL, 1.7 mmol), and(S)-(+)-S-methyl-5-phenylsulfoximine (162 mg, 1.0 mmol) in 4.0 mL DMF atroom temperature was added BOP (423 mg, 0.96 mmol). The solution wasstirred 30 minutes, then heated at 60° C. for 30 minutes, and thencooled back to room temperature. After 19 hours, the mixture wasdissolved in EtOAc, washed with Na₂CO₃ solution, H₂O, brine, dried withanhydrous Na₂SO₄ and rotary evaporated. The yellow foam was purified bychromatography (silica gel, CHCl₃/EtOAc) to give the title compound as alight yellow solid (260 mg, 84%).

Step 2(S)-2-amino-5-[(3-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide

To a degassed solution containing(S)-2-amino-5-bromo-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide(106 mg, 0.3 mmol) and 3-hydroxyphenylacetylene (50 mg, 0.42 mmol) in2.0 mL EtOAc at room temperature was added triethylamine (0.13 mL, 0.9mmol), dichlorobis(triphenylphosphine)palladium(II) (21 mg, 0.03 mmol),and copper(I) iodide (6 mg, 0.03 mmol). The reaction was stirred at 70°C. for 3.3 hours. Additional 3-hydroxyphenylacetylene was added (50 mg,0.42 mmol) and then again at 5.3 hours (75 mg, 0.63 mmol). The reactionwas cooled to room temperature, and after 23 hours additionaldichlorobis(triphenylphosphine)palladium(II) (20 mg, 0.03 mmol) wasadded. The reaction was heated to 60° C. and 3-hydroxyphenylacetylene(120 mg, 1.0 mmol) in 0.7 mL EtOAc (degassed) added dropwise over 7minutes. The heat was removed after 1 hour and the reaction stirred anadditional 22 hours at room temperature. The reaction was dissolved inEtOAc and washed with H₂O. The EtOAc layer was extracted with 2% aqueousHCl. The combined acidic aqueous layers were washed with 30%EtOAc/hexane and then made basic with Na₂CO₃. The basic aqueous layerwas extracted with EtOAc. Then the combined organic layers washed withbrine, dried with anhydrous Na₂SO₄ and concentrated. The yellow oil waspurified by chromatography (silica gel, CHCl₃/EtOAc) to give the titlecompound as a white solid (5 mg, 4%).

EXAMPLE 470 Step 1(S)-trimethyl{[methyl(oxo)phenyl-λ⁶-sulfanylidene]amino}silane

To a stirred pre-warmed solution of(S)-(+)-S-methyl-5-phenylsulphoximine (3 g, 18.7 mmol) in acetonitrile(2 mL) at 65° C. was added (trimethylsilyl)diethylamine (4.12 g, 21.1mmol) dropwise via a syringe. The reaction was maintained at 65° C. andstirred for 3 hours. Additional amount of (trimethylsilyl)diethylamine(2 mL, 10.2 mmol) was added and the reaction mixture was stirred at 65°C. overnight. The reaction was then concentrated under reduced pressureand dried under vacuum to give the title compound. This material wasused directly in next step of the synthesis without furtherpurification.

Step 2 (S)-Ethyl[S-phenyl-N-(trimethylsilyl)sulfonimidoyl]acetate

To a 100 mL round bottom flask equipped with a magnetic stir-bar and arubber septum was added a solution of 2,2,6,6-tetra-methylpiperidine(8.91 mL, 52.5 mmol) in anhydrous THF (22 mL). The solution was cooledto 0° C. and was treated with n-BuLi (18 mL, 45 mmol) (2.5 M in hexanes)via a syringe. The resulting solution was stirred for 10 min at 0° C.,cooled to −78° C., and treated dropwise with a solution of(S)-trimethyl{[methyl(oxo)phenyl-λ⁶-sulfanylidene]amino}silane (18.7mmol) in THF (10 mL). The reaction mixture was stirred at −78° C. for 30min and then was treated with ethyl chloroformate (5.16 mL, 52.5 mmol)dropwise. The reaction mixture was stirred for an hour and warmed toroom temperature. The reaction mixture was treated with saturatedaqueous NH₄Cl (2.5 mL). The white solid which formed was collected byfiltration and discarded. The filtrate was treated with additionalsaturated aqueous NH₄Cl solution and the resulting mixture was stored ina −20° C. fridge for 15 hours. The organic layer was collected andconcentrated to give the title compound. This material was used directlyin the next step of the synthesis.

Step 3 (S)-Ethyl(S-phenylsulfonimidoyl)acetate

A solution of Ethyl[S-phenyl-N-(trimethylsilyl)sulfonimidoyl]acetate(18.7 mmol, obtained as crude oil from step 2) in MeOH—H₂O (10:1, 7.5mL) was treated with cesium fluoride (0.25 g, 1.65 mmol) in one portion.The reaction mixture was heated to 50° C. and stirred for 2 hours. Thereaction mixture was concentrated, the residue absorbed to silica geland purified by chromatography (silica gel, EtOAc-Hexane, Et₃N 0.1%).The product containing fractions were concentrated to give the titlecompound as a pale yellow oil (1.65 g, 39% for steps 1-3).

Step 4 (S)-Ethyl{N-[(5-bromopyridin-3-yl)carbonyl]-S-phenylsulfonimidoyl}acetate

To a solution of 5-bromonicotinic acid (343 mg, 1.66 mmol) in anhydrousDMF (5.5 mL) was added N,N-diisopropylethylamine (0.58 mL, 3.32 mmol)and ethyl(S-phenylsulfonimidoyl)acetate (415 mg, 1.83 mmol) followed bythe final addition of(benzotriazol-1-yloxy)-tris(dimethylamino)-phosphoniumhexafluorophosphate (0.81 g, 1.83 mmol). The reaction mixture wasstirred at room temperature for 20 min, and then partitioned betweensaturated aqueous NaHCO₃ and EtOAc. The organic layer was separated andwashed once with brine and dried over anhydrous Na₂SO₄. The organiclayer was concentrated and the residue purified by chromatography(silica gel, gradient elution (5:1 Hexane/EtOAc to 3:1 Hexane/EtOAc).The product containing fractions were concentrated to give the titlecompound as a white solid (230 mg, 34%).

Step 5(S)-Ethyl[N-({5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate

A solution ethyl{N-[(5-bromopyridin-3-yl)carbonyl]-S-phenylsulfonimidoyl}acetate (216mg, 0.52 mmol) and 3-hydroxyphenylacetylene (0.052 mL, 0.79 mmol) inanhydrous DMF (3 mL) was treated with triethylamine (0.22 mL, 1.58mmol). The reaction mixture was degassed (alternating vacuum and argon)and PdCl₂(Ph₃P)₂ (36.9 mg, 0.052 mmol) and triphenylphosphine (3.4 mg,0.013 mmol) were added. The reaction mixture was degassed (alternatingvacuum and argon) and placed under an atmosphere of 1:3 Argon/hydrogenatmosphere. Copper(1⁺) iodide was added and the reaction mixture washeated at 60° C. for 50 min. The brown reaction mixture was partitionedbetween saturated aqueous NaHCO₃ and EtOAc. The organic layer wascollected and washed further with saturated aqueous NaHCO₃ (1×), brine(1×), and dried over anhydrous Na₂SO₄. The residue was purified bychromatography (silica gel, 50:1 CHCl₃:MeOH). The product containingfractions were concentrated to give the title compound as a light yellowsolid (220 mg, 94%).

EXAMPLE 471(S)-N-[(2-{[2-(diethylamino)ethyl]amino}-2-oxoethyl)(oxo)phenyl-λ⁶-sulfanylidene]-5-[(3-hydroxyphenyl)ethynyl]nicotinamide

(S)-Ethyl[N-({5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate(73 mg, 0.16 mmol) in anhydrous MeOH (1.5 mL) was addedN,N-diethylethylenediamine (0.12 mL, 0.84 mmol) dropwise. The reactionmixture was heated at 30° C. for 4 hours. The reaction mixture wasevaporated and the residue was partitioned between EtOAc and saturatedaqueous NaHCO₃. The organic layer was washed once with brine, dried(anhydrous Na₂SO₄), concentrated. The residue was purified bychromatography (silica gel, 50:1 CHCl₃:MeOH to 10:1 CHCl₃:MeOH). Theproduct containing fractions were concentrated to give the titlecompound as a foamy solid (50 mg, 59%).

EXAMPLE 472(S)-N-[{2-[(2-hydroxyethyl)(methyl)amino]-2-oxoethyl}(oxo)phenyl-λ⁶-sulfanylidene]-5-[(3-hydroxyphenyl)ethynyl]nicotinamide

In a manner similar to that described for Example 471,(S)-Ethyl[N-({5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate(65 mg, 0.14 mmol) and 2-(methylamino)ethanol (0.1 mL, 1.2 mmol) werereacted to give the title as clear oil (42 mg, 61%).

EXAMPLE 473 5-[(3-hydroxyphenyl)ethynyl]-N-{[2-(methylamino)-2-oxoethyl](oxo)phenyl-λ⁶-sulfanylidene}nicotinamide

In a manner similar to that described for Example 471,(S)-Ethyl[N-({5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate(50 mg, 0.11 mmol) and methylamine (2.0 M solution in MeOH, 0.5 mL, 1.0mmol) were reacted to give the title compound as colorless oil (43 mg,90%).

EXAMPLE 474N-[{2-[(2-hydroxyethyl)amino]-2-oxoethyl}(oxo)phenyl-λ⁶-sulfanylidene]-5-[(3-hydroxyphenyl)ethynyl]nicotinamide

In a manner similar to that described for Example 471,(S)-Ethyl[N-({5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate(75 mg, 0.17 mmol) and ethanolamine (0.05 mL, 0.84 mmol) were reacted togive the title compound as colorless oil (63 mg, 81

EXAMPLE 475N-[{2-[(2-amino-2-oxoethyl)amino]-2-oxoethyl}(oxo)phenyl-λ⁶-sulfanylidene]-5-[(3-hydroxyphenyl)ethynyl]nicotinamide

In a manner similar to that described for Example 471,(S)-Ethyl[N-({5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate(75 mg, 0.17 mmol) and glycinamide hydrochloride (95 mg, 0.84 mmol) werereacted to give the title compound as colorless oil (40 mg, 50%).

EXAMPLE 476(S)-5-[(2-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N-[methyl(oxido)phenyl--sulfanylidene]nicotinamide

Step 1 N-(3-ethynylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide

In a manner similar to that described in Example 457,2,5-dimethyl-2H-pyrazole-3-carbonyl chloride (0.135 g, 0.854 mmol) wasand 2-ethynyl-phenylamine (0.100 g, 0.854 mmol) were reacted to give thetitle compound as a tan solid (0.101 mg, 53%).

Step 2(S)-5-[(2-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N-[methyl(oxido)phenyl--sulfanylidene]nicotinamide

In a manner similar to that described in Example 460 (step 2)N-(3-ethynylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (0.0354 g,0.222) and (S)-5-bromo-N-[methyl(oxido)phenyl-

-sulfanylidene]nicotinamide (0.050 g, 0.148 mmol) reacted to give thetitle compound as a white solid (0.025 g, 34%).

EXAMPLE 477(S)-5-({2-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)-N-[methyl(oxido)phenyl--sulfanylidene]nicotinamide

Step 1 3-Methyl-furan-2-carboxylic acid (2-ethynyl-phenyl)-amide

In a manner similar to that described in Example 458 (step 1),3-methylthiophene-2-carboxylic acid (0.100 g, 0.794 mmol) and2-ethynyl-phenylamine (0.093 g, 0.794 mmol) were reacted to give thetitle compound as a tan solid (0.110 g, 56%).

Step 2(S)-5-({2-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)-N-[methyl(oxido)phenyl--sulfanylidene]nicotinamide

In a manner similar to that described for Example 460 (step 2),(S)-5-bromo-N-[methyl(oxido)phenyl-

-sulfanylidene]nicotinamide (0.050 g, 0.148 mmol) and3-methyl-furan-2-carboxylic acid (2-ethynyl-phenyl)-amide (0.050 g,0.222 mmol) were reacted to give the title compound (0.031 g, 43%).

EXAMPLE 478(S)-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)amino]carbonyl}phenyl)ethynyl]-N-[methyl(oxido)phenyl--sulfanylidene]nicotinamide

Step 1 N-(2,5-Dimethyl-2H-pyrazol-3-yl)-3-ethynyl-benzamide

3-Ethynylbenzoic acid (0.1 g, 0.685 mmol) was added to a dry 50 mL roundbottom flask and dissolved in DMF (6.85 mL). To the resulting solutionwas added 1,3-dimethyl-1H-pyrazol-5-amine (0.076 g, 0.685 mmol),followed by BOP (0.393 g, 0.890 mmol), and 0.238 mL of DIPEA (1.37mmol). This reaction mixture was heated to 50° C. for 3 h. Afterallowing the reaction to cool to room temperature it was taken up inEtOAc (15 mL) and extracted with brine (3×15 mL). The EtOAc layer wasthen washed with saturated aqueous NaHCO₃ (2×15 mL). The organics weredried over anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo.The crude residue was purified via column chromatography (silica gel,gradient eluant mixture of EtOAc in Hexanes: 0% to 100% EtOAc) affordingN-(1,3-dimethyl-1H-pyrazol-5-yl)-3-ethynylbenzamide (0.128 g, 78%).

Step 2(S)-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)amino]carbonyl}phenyl)ethynyl]-N-[methyl(oxido)phenyl--sulfanylidene]nicotinamide

In a manner similar to that described in Example 460 (step 2),(S)-5-bromo-N-[methyl(oxido)phenyl-

-sulfanylidene]nicotinamide (0.141 g, 0.418 mmol) andN-(1,3-dimethyl-1H-pyrazol-5-yl)-3-ethynylbenzamide (0.1 g, 0.418 mmol)were reacted to give the title compound (0.126 g, 61%).

EXAMPLE 479(S)-5-({3-[(methoxyamino)carbonyl]phenyl}ethynyl)-N-[methyl(oxido)phenyl--sulfanylidene]nicotinamide

Step 1 3-Ethynyl-N-methoxy-benzamide

In a manner similar to that described for Example 478 (step 1),3-ethynylbenzoic acid (0.1 g, 0.685 mmol) and O-methylhydroxylaminehydrogen chloride (0.057 g, 0.685 mmol) were reacted to give the titlecompound (0.128 g, 61%).

Step 2(S)-5-({3-[(methoxyamino)carbonyl]phenyl}ethynyl)-N-[methyl(oxido)phenyl--sulfanylidene]nicotinamide

In a manner similar to that described in Example 460 (step 2),(S)-5-bromo-N-[methyl(oxido)phenyl-

-sulfanylidene]nicotinamide (0.100 g, 0.295 mmol) and3-Ethynyl-N-methoxy-benzamide (0.106 g, 0.442 mmol) were reacted to givethe title compound yield (0.126 g, 86%).

EXAMPLE 480 Methyl3-{4-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]-amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]phenyl}-propanoate

Step 15-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)-ethynyl]nicotinicacid

In a 50 mL round bottom flask,N-(3-ethynylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (0.888 g,3.71 mmol) and 5-bromo nicotinic acid (0.50 g, 2.47 mmol) were dissolvedin DMF (15 mL) The mixture was then degassed by bubbling N_(2(g))through it for ˜20 min. The mixture was then treated sequentially withNEt₃ (1.37 mL, 9.90 mmol), Pd(PPh₃)₂Cl₂ (0.173 g, 0.247 mmol) and CuI(0.094 g, 4.95 mmol). The reaction mixture was allowed to stir at 50° C.for 4 h. The reaction mixture was diluted with EtOAc (25 mL) causing apale yellow precipitate to form. The white precipitate was filtered offgiving the title compound (0.105 g, 12%).

Step 2 Methyl 3-[4-(methylthio)phenyl]propanoate

In a 100 mL round bottom flask, 3-(4-(methylthio)phenyl)propanoic acid(1.00 g, 5.10 mmol) was dissolved in DMF (17 mL) under N_(2(g)). CDI(1.24 g, 7.65 mmol) was then added to the reaction mixture and theresulting mixture was allowed to stir at room temperature for ˜45 min.MeOH (6 mL) was then added in dropwise fashion to the reaction. Thereaction was allowed to stir for an additional 1 h, after which time itwas extracted with EtOAc (3×50 mL) and brine (3×50 mL). The combinedorganic extracts were dried over anhydrous Na₂SO_(4(s)), filtered andconcentrated. The crude product was purified by column chromatography(silica gel, gradient elution mixture: 10% EtOAc in Hexanes to 0100%EtOAc) to give the title compound (0.771 g, 72%).

Step 3 Methyl 3-[4-(methylsulfinyl)phenyl]propanoate

In a 250 mL round bottom flask, methyl3-(4-(methylthio)phenyl)propanoate (0.50 g, 2.38 mmol) was dissolved inMeOH under a N_(2(g)). The resulting solution was cooled to 0° C., then0.5 M NaIO₄ (4.76 mL, 2.38 mmol) was added dropwise to the cooledsolution causing the formation of a white precipitate. The reaction wasallowed to warm to room temperature. When HPLC indicated completeconsumption of starting thioether, the reaction was filtered and thefiltrate was concentrated. The resulting residue was taken up in CHCl₃(25 mL) then extracted with brine. The brine layer was subsequentlyextracted with CHCl₃ (2×25 mL). The combined organic extracts were thendried over anhydrous Na₂SO_(4(s)), filtered and concentrated. Theresulting sulfoxide was then purified by passing through a plug ofsilica using EtOAc/Hexanes as eluant affording methyl3-(4-(methylsulfinyl)phenyl)propanoate (0.436 g, 81%).

Step 4 Methyl3-{4-[S-methyl-N-(trifluoroacetyl)sulfonimidoyl]phenyl}-propanoate

In a 100 mL round bottom flask, methyl3-(4-(methylsulfinyl)phenyl)propanoate (0.4 g, 1.77 mmol) was added toCH₂Cl₂ (18 mL). Subsequently the reaction was treated with MgO (0.285 g,7.08 mmol), trifluoroacetamide (0.400 g, 3.54 mmol), PhI(OAc)₄ (0.884 g,2.66 mmol), and Rh₂(OAc)₄ (19.55 mg, 0.0443 mmol). The suspension wasstirred overnight then filtered through celite. The filtrate was theconcentrated. The resulting residue was purified via columnchromatography (silica gel, gradient eluant mixture: 20% EtOAc inhexanes to 100% EtOAc) to give the title compound (0.294 g, 69%).

Step 5 Methyl 3-[4-(S-methylsulfonimidoyl)phenyl]propanoate

Methyl 3-{4-[S-methyl-N-(trifluoroacetyl)sulfonimidoyl]phenyl}propanoate(0.200 g, 0.653 mmol) was dissolved in MeOH (3 mL). K₂CO₃ (0.450 g, 3.27mmol) was added to the solution, and the resulting suspension wasallowed to stir for 5 minutes. The suspension was filtered and thefiltrate was concentrated. The residue was dissolved in EtOAc and driedover anhydrous anhydrous Na₂SO_(4(s)) to give the title compound (0.147g, 93%).

Step 6

Methyl3-{4-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]-amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]phenyl}-propanoate

A solution of5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)-ethynyl]nicotinicacid (0.149 g, 0.414 mmol) in DMF (4 mL) was treated with methyl3-(4-(S-methylsulfonimidoyl)phenyl)propanoate (0.100 g, 0.414 mmol),followed by BOP (0.238 g, 0.539 mmol) and DIPEA (0.144 mL, 0.830 mmol).The reaction mixture was heated to 50° C. for 3 h. After allowing thereaction to cool to room temperature it was taken up in EtOAc (10 mL)and extracted with brine (3×10 mL). The EtOAc layer was then washed withsaturated aqueous Na₂CO₃ (2×10 mL). The organic layer was dried overanhydrous Na₂SO_(4(s)), filtered and concentrated. The crude residue waspurified via column chromatography (silica gel, gradient elution, EtOAcin Hexanes: 0% to 100% EtOAc) affording the title compound (0.108 g,45%).

EXAMPLE 4813-{4-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}-phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]phenyl}propanoicacid

A solution of Methyl3-{4-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}-phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]phenyl}propanoate(0.075 g, 0.129 mmol) in THF (3 mL) was cooled to 0° C. and slowlytreated with 0.5M NaOH (1.29 mL, 0.643 mmol). The reaction mixture wasallowed to slowly come to room temperature. Once the reaction was doneby TLC, the reaction was acidified with acetic acid and then extractedwith EtOAc (20 mL) and H₂O (20 mL). The organic layer was dried overanhydrous Na₂SO_(4(s)), filtered, and concentrated to give the titlecompound (0.052 g, 71%).

EXAMPLE 482N-[(4-{[3-(dimethylamino)propyl]amino}phenyl)(methyl)oxido--sulfanylidene]-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide

Step 1 tert-Butyl[4-(methylthio)phenyl]carbamate

4-Methylsulfanyl-phenylamine (0.5 g, 3.59 mmol) was dissolved in THF (12mL) The resulting solution was treated with di-tert butyl dicarbonate(1.02 g, 4.67 mmol) and then with TEA (1.5 mL, 10.78 mmol). The reactionwas heated at 50° C. for 3 h and then allowed to cool to roomtemperature. The cool reaction mixture was taken up in EtOAc (20 mL) andextracted with H₂O (20 mL). The organic layer was further washed with asaturated aqueous solution of NaHCO₃ (20 mL). The organic layer wasdried over anhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo.The crude mixture was purified via column chromatography (gradienteluant mixture of EtOAc in Hexanes: 0% to 100% EtOAc) to the titlecompound (0.652 g, 76%).

Step 2 tert-Butyl[4-(methylsulfinyl)phenyl]carbamate

In a manner similar to that described in Example 480 (step 3),tert-Butyl[4-(methylthio)phenyl]carbamate (0.650 g, 2.72 mmol) wasconverted to the title compound (0.347 g, 50%).

Step 3 tert-butyl{4-[S-methyl-N-(trifluoroacetyl)sulfonimidoyl]phenyl}-carbamate

In a manner similar to that described in Example 480 (step 4),tert-Butyl[4-(methylsulfinyl)phenyl]carbamate (0.300 g, 1.18 mmol) wasconverted to the title compound (0.224 g, 52%).

Step 4 tert-Butyl[4-(S-methylsulfonimidoyl)phenyl]carbamate

In a manner similar to that described in Example 480 (step 5),tert-butyl{4-[S-methyl-N-(trifluoroacetyl)sulfonimidoyl]phenyl}-carbamate (0.224g, 0.612 mmol) was converted to the title compound (0.150 g, 91%).

Step 5 tert-butyl(4-{N-[(5-bromopyridin-3-yl)carbonyl]-S-methylsulfonimidoyl}phenyl)carbamate

In a manner similar to that described in Example 480 (step 6),tert-Butyl[4-(S-methylsulfonimidoyl)phenyl]carbamate (0.141 g, 0.522mmol) and 5-bromonicotinic acid (0.104 g, 0.522 mmol), were converted tothe title compound (0.177 g, 75%).

Step 6N-[(4-{[tertbutyloxycarbonyl]amino}phenyl)(methyl)oxido--sulfanylidene]-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide

In a manner similar to that described in Example 460, tert-butyl(4-{N-[(5-bromopyridin-3-yl)carbonyl]-S-methylsulfonimidoyl}phenyl)carbamate(0.158 g, 0.349 mmol) and 2,5-dimethyl-2H-pyrazole-3-carboxylic acid(3-ethynyl-phenyl)-amide (0.125 g, 0.0524 mmol) were reacted to give thetitle compound (0.108 g, 51%).

Step 7N-[(4-{amino}phenyl)(methyl)oxido--sulfanylidene]-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide

The BOC protected N-[(4-{amino}phenyl)(methyl)oxido-

-sulfanylidene]-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide(0.108 g, 0.177 mmol) was dissolved in CHCl₃ (3.5 mL) and the resultingsolution was cooled to 0° C. The resulting reaction mixture was thentreated slowly with CF₃COOH (1 mL) and allowed to stir while warming tort. The reaction mixture was stirred at room temperature for 4 hours andthen was diluted with CHCl₃ (5 mL). The organic mixture was extractedwith H₂O (5 mL), then with a saturated aqueous solution of NaHCO₃ (2×5mL) and then with brine (5 mL). The organic layer was then dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo give thetitle compound (0.086 g, 95%).

Step 8N-[(4-{[3-(dimethylamino)propyl]amino}phenyl)(methyl)oxido--sulfanylidene]-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide

N-[(4-{amino}phenyl)(methyl)oxido-

-sulfanylidene]-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide(0.085 g, 0.168 mmol) was dissolved in dioxane (1.7 mL) then treatedwith (3-Chloro-propyl)-diethyl-amine (0.047 g, 0.252 mmol) and TEA(0.070 mL, 0.504 mmol). The reaction mixture was then heated to 100° C.for 48 h then cooled to room temperature. The cooled mixture wasdissolved in EtOAc (5 mL) and then extracted with water (3×5 mL) andwith brine (5 mL). The organic layer was dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo. The crude mixture waspurified via column chromatography (gradient eluant mixture of MeOH inEtOAc: 0% to 20% MeOH) to give the title compound (4 mg, 3.5%).

EXAMPLE 483 Methyl3-[4-(S-methyl-N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}sulfonimidoyl)phenyl]propanoate

In a manner similar to that described in Example 480 (step 6), Methyl3-(4-(S-methylsulfonimidoyl)phenyl)propanoate (0.25 g, 1.037 mmol) and5-((3-(3-methylfuran-2-carboxamido)phenyl)ethynyl)nicotinic acid (0.326g, 0.943 mmol) reacted to give the title compound (0.508 g, 86%).

EXAMPLE 4843-[4-(S-methyl-N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)pyridin-3-yl]carbonyl}sulfonimidoyl)phenyl]propanoicacid

In a manner similar to that described in Example 481, Methyl3-(4-(S-methyl-N-(5-((3-(3-methylfuran-2-carboxamido)phenyl)ethynyl)-nicotinoyl)-sulfonimidoyl)phenyl)propanoate(0.4 g, 0.703 mmol) was converted to the title compound (0.350 g, 89%).

EXAMPLE 4855-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)-N-{methyl[4-(3-morpholin-4-yl-3-oxopropyl)phenyl]oxido--sulfanylidene}nicotinamide

3-[4-(S-methyl-N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)pyridin-3-yl]carbonyl}sulfonimidoyl)phenyl]propanoicacid (0.050 g, 0.090 mmol) was dissolved in DMF (1 mL) then treated withBOP (0.051 g, 0.117 mmol) and TEA (0.050 mL, 0.360 mmol) and allowed tostir for 20 min. Morpholine (0.015 mL, 0.180 mmol) was then added andthe reaction was allowed to stir for an additional 4 h. The resultingreaction mixture was dissolved in EtOAc (5 mL) and then extracted withbrine (2×5 mL). The organic layer was then dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo. The crude mixture wasthen purified via column chromatography (silica gel, gradient eluantmixture of MeOH in EtOAc: 0% to 0% MeOH) give the title compound (0.023g, 41%).

EXAMPLE 486N-[(4-{3-[(2,3-dihydroxypropyl)(methyl)amino]-3-oxopropyl}phenyl)-(methyl)oxido--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)nicotinamide

In a manner similar to that described in Example 485,3-[4-(S-methyl-N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)pyridin-3-yl]carbonyl}sulfonimidoyl)-phenyl]propanoicacid (0.050 g, 0.090 mmol) and 3-methylamino-propane-1,2-diol (0.050 mL,0.520 mmol) were reacted to give the title compound (0.020 g, 35%).

EXAMPLE 487N-[{4-[3-(3-hydroxypyrrolidin-1-yl)-3-oxopropyl]phenyl}(methyl)oxido--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)nicotinamide

In a manner similar to that described in Example 485,3-[4-(S-methyl-N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)pyridin-3-yl]carbonyl}sulfonimidoyl)-phenyl]propanoicacid (0.050 g, 0.090 mmol) and pyrrolidin-3-ol (0.016 g, 0.180 mmol)were reacted to give the title compound (0.015 g, 27%).

EXAMPLE 488N-{[4-(3-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}-3-oxopropyl)phenyl](methyl)oxido--sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide

In a manner similar to that described in Example 485,3-[4-(S-methyl-N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)pyridin-3-yl]carbonyl}sulfonimidoyl)-phenyl]propanoicacid (0.050 g, 0.090 mmol) and 2-(2-piperazin-1-yl-ethoxy)-ethanol(0.030 mL, 0.180 mmol) were reacted to give the title compound (0.030 g,47%).

EXAMPLE 489 2-hydroxyethyl3-[4-(S-methyl-N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}sulfonimidoyl)phenyl]propanoate

3-[4-(S-methyl-N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)pyridin-3-yl]carbonyl}sulfonimidoyl)phenyl]propanoicacid (0.150 g, 0.270 mmol) was dissolved in DMF (2.7 mL) then treatedwith EDCI (0.062 g, 0.324 mmol) and DMAP (0.003 g, 0.027 mmol) andallowed to stir at 60° C. for 30 min. Ethylene glycol (3 mL) was thenadded and the reaction was allowed to stir for 4 hours. The reactionmixture was then cooled to room temperature and dissolved in EtOAc (10mL) and extracted with brine (3×10 mL). The organic layer was dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo. The crudemixture was then redissolved in EtOAc (1 mL) and triturated with Hexanes(20 mL) causing the product to precipitate out. The resulting whitesolid to give the title compound (0.125 g, 77%).

EXAMPLE 490 N-{[4-(hydroxymethyl)phenyl](methyl)oxido--sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)nicotinamide

Step 1 tert-butyl(dimethyl) {[4-(methylthio)benzyl]oxy}silane

t-Butyldimethylsilyl chloride (2.45 g, 16.2 mmol) was dissolved in DMF(3.25 mL) then treated with imidazole (2.21 g, 32.4 mmol). The reactionmixture was allowed to stir for 20 minutes before4-Methylsulfanyl-phenyl)-methanol (0.5 g, 3.25 mmol) was added. Thereaction was stirred overnight and then dissolved in EtOAc (20 mL). Theorganic mixture was extracted with H₂O (3×10 mL). The organic organiclayer was dried over anhydrous Na₂SO_(4(s)), filtered and concentratedin vacuo. The crude residue was then purified via column chromatography(gradient eluant mixture of EtOAc in Hexanes: 0% to 100% EtOAc to givethe title compound (0.828 g, 95%).

Step 2 tert-butyl(dimethyl) {[4-(methylsulfinyl)benzyl]oxy}silane

In a manner similar to that described in Example 480 (step 3),tert-Butyl-dimethyl-(4-methylsulfanyl-benzyloxy)-silane (0.828 g, 3.08mmol), was converted to the title compound in 82% yield (0.716 g, 82%).

Step 3 tert-Butyl(dimethyl){[4-(S-methyl-N-(trifluoroacetyl)-sulfonimidoyl)benzyl]oxy}silane

In a manner similar to that described in Example 480 (step 4),tert-butyl(dimethyl) {[4-(methylsulfinyl)benzyl]oxy}silane (0.716 g,2.52 mmol) was converted to the title compound (0.524 g, 52%).

Step 4 tert-Butyl(dimethyl) {[4-(S-methylsulfonimidoyl)benzyl]oxy}silane

In a manner similar to that described in Example 480 (step 5),tert-Butyl(dimethyl){[4-(S-methyl-N-(trifluoroacetyl)-sulfonimidoyl)benzyl]oxy}silane (0.524g, 1.32 mmol) was converted to the title compound (0.385 g, 97%).

Step 5N-{[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl](methyl)oxido--sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)nicotinamide

In a manner similar to that described in Example 480 (step 6),tert-Butyl(dimethyl) {[4-(S-methylsulfonimidoyl)benzyl]oxy}silane (0.485g, 1.62 mmol) and5-((3-(3-methylfuran-2-carboxamido)phenyl)ethynyl)nicotinic acid (0.561g, 1.62 mmol) were reacted to give the title compound (0.722 g, 71%).

Step 6 N-{[4-(hydroxymethyl)phenyl](methyl)oxido--sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)nicotinamide

N-{[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl](methyl)oxido-

-sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)nicotinamide(0.722 g, 1.15 mmol) was dissolved in THF (2.3 mL). The resultingsolution was treated with 1M solution of TBAF in THF (2.3 mL, 2.30 mmol)causing the mixture to turn black in color. The mixture was allowed tostir for 1 h, subsequently dissolved in EtOAc (10 mL) and extracted withH₂O (3×15 mL). The organic layer was dried over anhydrous Na₂SO_(4(s)),filtered and concentrated in vacuo. The crude product was purified viacolumn chromatography (gradient eluant mixture of EtOAc in Hexanes: 0%to 100% EtOAc) to afford the title compound in 94% yield (0.350 g, 0.682mmol).

EXAMPLE 491N-{[4-({4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}methyl)phenyl](methyl)oxido--sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide

Step 1N-{[4-(Bromomethyl)phenyl](methyl)oxido--sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide

N-{[4-(hydroxymethyl)phenyl] (methyl)oxido-

-sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide(0.1 g, 0.195 mmol) and CBr₄ (0.097 g, 0.293 mmol) were dissolved inCH₂Cl₂ (0.485 mL) and the resulting solution was cooled to 0° C. PPh₃(0.858 g, 0.293 mmol) was dissolved in CH₂Cl₂ (0.250 mL) and then addeddropwise to the 0° C. reaction mixture. Subsequently the reaction wasallowed to warm to room temperature and stir for ˜1.5 h. The reactionwas then diluted with CH₂Cl₂ (5 mL) and the resulting organic mixturewas washed with a saturated aqueous solution of NaHCO₃ (5 mL), then withbrine (5 mL). The organic layer was dried anhydrous Na₂SO_(4(s)),filtered and concentrated in vacuo. The crude product was then taken onwithout further purification.

Step 2 N-{[4-({4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}methyl)phenyl](methyl)-oxido--sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide

Crude N-{[4-(Bromomethyl)phenyl] (methyl)oxido-

-sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamidewas dissolved in THF (2 mL). 2-(2-piperazin-1-yl-ethoxy)-ethanol (0.064g, 0.390 mmol) and TEA (0.054 mL, 0.390 mmol) were then added to thesolution and the resulting reaction mixture was allowed to stir for 1 hat rt. The reaction mixture, subsequently, was dissolved in EtOAc andthen extracted with H₂O (2× mL). The organic layer was dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo. The crudeproduct was purified via column chromatography (gradient eluant mixtureof MeOH in EtOAc: 0% to 20% MeOH) to afford the title compound (0.064 g,49% overall for step 1 and 2).

EXAMPLE 492 Methyl3-{4-[N-({6-amino-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]phenyl}propanoate

In a manner similar to that described in Example 480 (step 6),6-Amino-5-{3-[(2,5-dimethyl-2H-pyrazole-3-carbonyl)-amino]-phenylethynyl}-nicotinicacid (0.250 g, 0.666 mmol) and methyl3-(4-(S-methylsulfonimidoyl)-phenyl)propanoate (0.160 g, 0.666 mmol)were reacted to give the title compound (0.167 g, 42%).

EXAMPLE 4933-{4-[N-({6-amino-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]-amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]phenyl}propanoicacid

In a manner similar to that described for Example 481, methyl3-{4-[N-({6-amino-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}-phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]-phenyl}propanoate(0.167 g, 0.280 mmol) was converted to the title compound (0.150 g,89%).

EXAMPLE 4943-[4-(N-{[6-amino-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)-pyridin-3-yl]carbonyl}-S-methylsulfonimidoyl)phenyl]propanoicacid

Step 16-Amino-5-{3-[(3-methyl-furan-2-carbonyl)-amino]-phenylethynyl}-nicotinicacid methyl ester

In a 4 mL vial, N-(3-ethynylphenyl)-3-methylfuran-2-carboxamide (0.607g, 2.70 mmol) and methyl 6-amino-5-iodonicotinate (0.5 g, 1.80 mmol)were dissolved in DMF (6 mL). The solution was degassed by bubblingN_(2(g)) through it for ˜30 min. To the degassed solution was addedDIPEA (1.25 mL, 7.19 mmol), followed by Pd(PPh₃)₂Cl₂ (0.126 g, 0.18mmol) and CuI (0.068 g, 0.360 mmol). The reaction mixture was allowed tostir at 50° C. for 3 h. The reaction mixture then was taken up in EtOAc(10 mL) and was extracted with brine (3×10 mL). The organic layers werecombined and concentrated in vacuo. The crude mixture was purified viacolumn chromatography (gradient eluant mixture of EtOAc in Hexanes: 25%to 100% EtOAc) to give the title compound as a white solid (0.554 g,82%).

Step 26-Amino-5-{3-[(3-methyl-furan-2-carbonyl)-amino]-phenylethynyl}-nicotinicacid

Methyl6-amino-5-((3-(3-methylfuran-2-carboxamido)phenyl)ethynyl)nicotinate(0.550 g, 1.47 mmol) was dissolved in THF (15 mL) and then treated with1.0 M NaOH (7.33 mL, 7.33 mmol). The reaction mixture was heated to 50°C. Once the reaction was done by TLC, the reaction was cooled to roomtemperature and then acidified with acetic acid. The reaction mixturewas taken up in of EtOAc (˜15 mL) then extracted with H₂O (2×15 mL). Thewater layer then was re-washed with EtOAc (˜15 mL) and the combinedorganic layers were dried over anhydrous Na₂SO_(4(s)). The mixture wasthen filtered and concentrated in vacuo to give the title compound(0.495 g, 1.37 mmol).

Step 3 Methyl3-[4-(N-{[6-amino-5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)pyridin-3-yl]carbonyl}-S-methylsulfonimidoyl)phenyl]propanoate

6-Amino-5-((3-(3-methylfuran-2-carboxamido)phenyl)ethynyl)nicotinic acid(0.1 g, 0.277 mmol) was dissolved in DMF (2.8 mL). EDCI (0.64 g, 0.332mmol) and DMAP (3.42 mg, 0.028 mmol) were then added and the reactionmixture was stirred at 60° C. for 20 minutes. Methyl3-(4-(S-methylsulfonimidoyl)-phenyl)propanoate (0.068 g, 0.277 mmol) wasthen added, and the reaction was allowed to stir for 3 hours at 60° C.The mixture was cooled to room temperature then taken up in EtOAc (10mL) and extracted with brine (3×10 mL). The organic layer was dried overanhydrous Na₂SO_(4(s)), filtered and concentrated in vacuo. The crudeproduct was then purified over silica purified via column chromatography(gradient eluant mixture of MeOH in EtOAc: 0% to 10% MeOH) to give thetitle compound (0.060 g, 37%).

Step 43-[4-(N-{[6-amino-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)-pyridin-3-yl]carbonyl}-S-methylsulfonimidoyl)phenyl]propanoicacid

In a manner similar to that described in Example 481, methyl3-(4-(N-(6-amino-5-((3-(3-methylfuran-2-carboxamido)phenyl)ethynyl)-nicotinoyl)-S-methylsulfonimidoyl)phenyl)propanoate(0.060 g, 0.103 mmol) was converted to the title compound in (0.040 g,68%).

EXAMPLE 4956-amino-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N-[methyl(oxido)phenyl--sulfanylidene]nicotinamideStep 1 N-(3-iodophenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide

To a solution of 3-iodoaniline (131 mg, 0.60 mmol) in 1.5 ml pyridine atroom temperature was added over 2 minutes a solution of1,3-dimethylpyrazole-5-carbonyl chloride (79 mg, 0.50 mmol) in 0.3 ml1,2-dichloroethane. The reaction was stirred at room temperature for 30minutes, quenched into a NaHCO₃ solution, and extracted into EtOAc. TheEtOAc solution was washed with NaHCO₃ solution, brine, dried withanhydrous Na₂SO₄ and rotary evaporated. The resultant gummy solid wasrecrystallized from hexane/EtOAc to give the title compound as solidwhite needles (135 mg, 80%).

Step 26-amino-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N-[methyl(oxido)phenyl--sulfanylidene]nicotinamide

A mixture of 6-amino-5-ethynyl-N-[methyl(oxido)phenyl-

-sulfanylidene]nicotinamide (42 mg, 0.14 mmol),N-(3-iodophenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (57 mg, 0.17mmol), triethylamine (0.049 ml, 0.35 mmol),

dichlorobis(triphenylphosphine)palladium(II) (8 mg, 0.011 mmol), andtriphenylphosphine (1.8 mg, 0.007 mmol) in 1.2 ml DMF at roomtemperature was degassed using a H₂/N₂ (1:1) mixture and thencopper(I)iodide (1.3 mg, 0.007 mmol) added. The reaction was stirred atroom temperature for 15 minutes and then partitioned between EtOAc andsaturated NaHCO₃/brine mixture. The EtOAc layer was washed withNaHCO₃/brine mixture, brine, dried with anhydrous Na₂SO₄ and rotaryevaporated. The orange oil was chromatographed eluting withhexane/acetone to give the title compound as a light tan solid (64 mg,90%).

EXAMPLE 496 Step 1 [3-(methylsulfinyl)phenyl]acetic acid

In a manner similar to that described in Example 480 (step 3),3-(methylthio)phenylacetic acid (2.55 g, 14.0 mmol) was converted togive the title compound as a light tan solid (2.36 g, 85%).

Step 2 Methyl[3-(methylsulfinyl)phenyl]acetate

A solution of [3-(methylsulfinyl)phenyl]acetic acid (1.31 g, 6.60 mmol)and carbonyldiimidazole (1.18 g, 7.26 mmol) in 25.0 mL THF was stirredat room temperature for 15 minutes, then methanol (2.1 mL, 52.8 mmol)was added. After 10 minutes the reaction was briefly warmed to nearreflux temperature, then allowed to cool to room temperature. After 20minutes, the reaction was partitioned between EtOAc and NaHCO₃/brinemixture. The EtOAc layer was washed with dilute brine, dilute HClsolution, brine, dried with anhydrous Na₂SO₄ and rotary evaporated togive the title compound as a yellow-orange oil (1.14 g, 82%).

Step 3Methyl{3-[S-methyl-N-(trifluoroacetyl)sulfonimidoyl]phenyl}acetate

In a manner similar to that described in Example 480 (step 4),methyl[3-(methylsulfinyl)phenyl]acetate (1.18 g, 5.54 mmol), wasconverted to the title compound as a white solid (1.23 g, 68%).

Step 4 Methyl[3-(S-methylsulfonimidoyl)phenyl]acetate

In a manner similar that described in Example 480 (step 5),methyl{3-[S-methyl-N-(trifluoroacetyl)sulfonimidoyl]phenyl}acetate (1.29g, 3.98 mmol) was converted to the title compound as a cloudy white oil(849 mg, 94%).

Step 5Methyl(3-{N-[(5-bromopyridin-3-yl)carbonyl]-S-methylsulfonimidoyl}phenyl)acetate

To a solution of 5-bromonicotinic acid (648 mg, 3.21 mmol),methyl[3-(S-methylsulfonimidoyl)phenyl]acetate (802 mg, 3.53 mmol), andcatalytic DMAP in 15.0 ml DMF at room temperature was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (738 mg,3.85 mmol). The reaction was stirred 1 hour at room temperature thenadded to EtOAc. The EtOAc solution was washed with dilute brine, NaHCO₃solution, brine, dilute HCl/brine mixture, brine/NaHCO₃ solution, driedwith anhydrous Na₂SO₄ and rotary evaporated. The oil was chromatographedeluting with CHCl₃/EtOAc to give viscous clear oil (994 mg, 75%).

Step 6methyl{3-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]phenyl}acetate

In a manner similar to that described in Example 460,methyl(3-{N-[(5-bromopyridin-3-yl)carbonyl]-S-methylsulfonimidoyl}phenyl)acetate(202 mg, 0.492 mmol) andN-(3-ethynylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (153 mg, 0.64mmol), were converted to the title compound as a light yellow solid foam(275 mg, 98%).

EXAMPLE 497{3-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]phenyl}aceticacid

A 50 ml THF solution ofmethyl{3-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]phenyl}acetate(216 mg, 0.38 mmol) and 0.5M NaOH (6.1 ml, 3.04 mmol) was stirred atroom temperature for 2 hours. The reaction was quenched with acetic acid(0.174 ml, 3.04 mmol) and rotary evaporated to remove the THF solvent.Additional impure lots of product (22 mg) were combined and the aqueousmixture partitioned between EtOAc and NaHCO₃ solution. The EtOAc layerwas extracted with another portion of NaHCO₃ solution. The combinedbasic aqueous layers were adjusted to pH 4 using 10% HCl and extractedwith EtOAc. The combined EtOAc layers were washed with brine, dried withanhydrous Na₂SO₄ and rotary evaporated. The off-white solid foam waschromatographed eluting with CHCl₃/MeOH and then recrystallized from amixture of CHCl₃/EtOAc/MeCN to give white solid (144 mg, 62%).

EXAMPLE 498 Step 1 3-(methylsulfinyl)benzoic acid

In a manner similar to that described in Example 480 (step 3),3-(methylthio)benzoic acid (3.03 g, 18.0 mmol) to give the titlecompound as a white solid (3.11 g, 94%).

Step 2 Methyl 3-(methylsulfinyl)benzoate

In a manner similar to that described in Example 496 (step 2),3-(methylsulfinyl)benzoic acid was converted to the title compound.

Step 3 Methyl 3-(S-methylsulfonimidoyl)benzoate

A solution of methyl 3-(methylsulfinyl)benzoate (3.23 g, 16.3 mmol),2,2,2-trifluoroacetamide (3.69 g, 32.6 mmol), magnesium oxide (1.97 g,48.9 mmol), rhodium(II) acetate dimer (0.18 g, 0.408 mmol), andiodobenzene diacetate (7.88 g, 24.5 mmol) in 150 ml dichloromethane wasstirred at room temperature. After 16 hours, the mixture was filteredpast filter agent (Celite), rinsed with chloroform, and rotaryevaporated. The sample was dissolved in EtOAc, washed with brine/diluteHCl, brine, dried with anhydrous Na₂SO₄ and rotary evaporated. Theyellow-orange oil was dissolved in 60 ml MeOH, K₂CO₃ (6.76 g, 48.9 mmol)added, and the mixture stirred at room temperature for 12 minutes. TheMeOH filtrate was decanted from the solids, which were then rinsed withMeOH and EtOAc. The pH of the combined organic filtrates were adjustedto pH 2 using 4% HCl, then the aqueous layer diluted by adding H₂O. Theaqueous layer was washed with 30% EtOAc in hexane, then the pH adjustedto pH 9 with saturated Na₂CO₃. The aqueous layer was extracted withCHCl₃, the combined CHCl₃ layers washed with brine, dried with anhydrousNa₂SO₄ and rotary evaporated to give the title compound as a light tansolid (2.58 g, 74%).

Step 4 Methyl3-{N-[(5-bromopyridin-3-yl)carbonyl]-S-methylsulfonimidoyl}benzoate

In a manner similar to that described in Example 480 (step 6),5-bromonicotinic acid and methyl 3-(S-methylsulfonimidoyl)benzoate werereacted to give the title compound.

Step 5 methyl3-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]benzoate

In a manner similar to that described in Example 460, methyl3-{N-[(5-bromopyridin-3-yl)carbonyl]-S-methylsulfonimidoyl}benzoate andN-(3-ethynylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide were reactedto give the title compound.

EXAMPLE 4993-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]benzoicacid

A 50 ml THF solution of methyl3-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]benzoate(228 mg, 0.41 mmol) and 0.5M NaOH (6.6 ml, 3.28 mmol) was stirred atroom temperature for 3 hours. The reaction was quenched with acetic acid(0.188 ml, 3.28 mmol) and rotary evaporated to remove the THF solvent.The aqueous solution was partitioned between EtOAc and dilute HCl/brinemixture, the EtOAc layer washed with brine, dried with anhydrous Na₂SO₄and rotary evaporated to white solid foam. The solid was combined withimpure product from another lot (14 mg) and recrystallized fromEtOAc/hexane to give the title compound as a white solid (147 mg, 62%).

EXAMPLE 5005-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N-[methyl(3-{[(2-morpholin-4-ylethyl)amino]carbonyl}phenyl)oxido-λ⁴-sulfanylidene]nicotinamide

A solution of3-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]benzoicacid (20 mg, 0.036 mmol) and 1,1′-carbonyldiimidazole (12 mg, 0.072mmol) in 0.8 ml THF was stirred at room temperature for 35 minutes. Then4-(2-aminoethyl)morpholine (0.009 ml, 0.072 mmol) was added, stirred 30minutes at room temperature, and the mixture added to EtOAc. The EtOAcsolution was washed with NaHCO₃ solution, brine, dried with anhydrousNa₂SO₄ and rotary evaporated. The clear film was chromatographed elutingwith CHCl₃/MeOH and then chromatographed again using a preparative TLCplate (eluted with 8:2/CHCl₃:MeOH) to afford an off-white solid foam (19mg, 81%).

EXAMPLE 5015-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N-[methyl(3-{2-[(2-morpholin-4-ylethyl)amino]-2-oxoethyl}phenyl)oxido--sulfanylidene]nicotinamide

In a manner similar to that described in Example 500,{3-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]phenyl}aceticacid and 4-(2-aminoethyl)morpholine were reacted to give the titlecompound (54%).

EXAMPLE 502N-{[3-({[2-(diethylamino)ethyl]amino}carbonyl)phenyl](methyl)oxido--sulfanylidene}-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide

To a solution of3-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]benzoicacid (52 mg, 0.096 mmol), 2-diethylaminoethylamine (0.016 ml, 0.115mmol), and N,N-diisopropylethylamine (0.034 ml, 0.192 mmol) in 3.0 mlDMF at room temperature was addedbenzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate(47 mg, 0.106 mmol). The reaction was stirred at room temperature for1.5 hours, and then partitioned between EtOAc and dilute brine. TheEtOAc layer was washed with saturated NaHCO₃ solution, dilute brine,dried with anhydrous Na₂SO₄ and rotary evaporated. The yellow oil(combined 7 mg impure product from another lot) was chromatographedeluting with EtOAc/MeOH, then rechromatographed using a preparative TLCplate (eluted with (1:1:2.5) CHCl₃:EtOAc:MeOH plus NH₄OH) to give thetitle compound as a white solid foam (28 mg).

EXAMPLE 503{3-[N-({6-amino-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]phenyl}aceticacid

A solution ofmethyl{3-[N-({6-amino-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]phenyl}acetate(13 mg, 0.021 mmol) and 1.0M NaOH (0.171 ml, 0.171 mmol) in 2.0 ml MeOHand 0.1 ml H₂O was stirred at room temperature for 1 hour 10 minutes.The pH of the mixture was adjusted to pH 4 using 10% HCl, brine added,and the aqueous extracted with EtOAc. The combined EtOAc layers werewashed with brine, dried with anhydrous Na₂SO₄ and rotary evaporated.The white solid was triturated with hot EtOAc to give white solid (11mg, 92%).

EXAMPLE 504 methyl3-[N-({6-amino-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]benzoate

To a solution of6-amino-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinicacid (68 mg, 0.18 mmol), methyl 3-(S-methylsulfonimidoyl)benzoate (42mg, 0.198 mmol), and N,N-diisopropylethylamine (0.063 ml, 0.36 mmol) in1.5 ml DMF at room temperature was addedbenzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate(88 mg, 0.198 mmol). The reaction was heated at 60° C. for 3.5 hours,then at 48° C. for 16.5 hours. The mixture was partitioned between EtOAcand dilute brine. The EtOAc layer was washed with NaHCO₃ solution,dilute HCl, NaHCO₃ solution, brine, dried with anhydrous Na₂SO₄ androtary evaporated. The dark foam was chromatographed eluting withhexane/acetone yielding light pink solid (38 mg, 37%).

EXAMPLE 5053-[N-({6-amino-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]benzoicacid

In a manner similar to that described in Example 503, methyl3-[N-({6-amino-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]benzoatewas converted to the title compound.

EXAMPLE 506N-[(3-hydroxypropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamideStep 1 (S)-tert-butyl(dimethyl) [3-(S-phenylsulfonimidoyl)propoxy]silane

To the sulfoximine (6.46 g, 41.62 mmol) solution in anhydrous CH₃CN (5mL) at 70° C. was added dropwise N,N-diethyl-trimethylsilylamine (1.2 eq˜1.5 eq). The reaction mixture was heated and stirred at thistemperature for one hour. It was then concentrated under reducedpressure to yield slightly brown oil (9.26 g) which was dried in-vacuo.The brown oil was dissolved in anhydrous THF (40 mL) and the resultingsolution was cooled to −78° C. followed by dropwise addition of nBuLi(17.1 mL, 2.5 M in hexanes). The reaction mixture was stirred 10 min at−78° C. and then 20 min at 0° C. After hexamethylphosphoramide (13.5 mL)was added, the reaction mixture was cooled back to −78° C. followed bydropwise addition of 2-bromoethoxy-tert-butyl-dimethylsilane over a fewminutes. The reaction mixture was stirred at −78° C. for about an hourand allowed to warm-up to room temperature within 4 hours. The reactionmixture was then concentrated at room temperature under reducedpressure. The oily residue was taken up in ether (500 mL), which wassubsequently washed with ice-water (2×300 mL), brine (1×), and driedwith anhydrous Na₂SO₄ overnight. The ether layer was decanted andconcentrated.

The crude oily residue was dissolved in MeOH—H₂O (16 mL, 10:1) followedby addition of CsF (1.24 g). The resulting reaction mixture was heatedto 50° C. for one hour. It was then concentrated under reduced pressureand the yellow oily residue was partitioned between EtOAc (500 mL) andH₂O (300 mL). The organic layer was separated and washed subsequentlywith H₂O (2×), brine (1×), and dried (Anhydrous Na₂SO₄). The EtOAc layerwas decanted and concentrated. The title compound was isolated as clearoil (6.65 g) upon gradient column chromatography (EtOAc-Hex:from 1:25 to1:2). The overall yield is 51% for total of three steps.

Step 2(S)-5-bromo-N-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)(oxido)phenyl--sulfanylidene]nicotinamide

To the solution of(S)-tert-butyl(dimethyl)[3-(S-phenylsulfonimidoyl)propoxy]silane (1.55g, 4.95 mmol) in DMF (15 mL) at room temperature was addedN,N-diisopropylethylamine (1.72 mL), 3-bromonicotinic acid (1.07 g), andfinally the coupling reagent,(benzotriazol-1-yloxy)-tris(dimethylamino)-phosphoniumhexafluorophosphate (2.48 g). The reaction was stirred for 15 min andthen poured into saturated aqueous NaHCO₃. The aqueous phase wasextracted with EtOAC (1×), which was subsequently washed with aqueousNaHCO₃, brine (1×), and dried with anhydrous Na₂SO₄. The organic layerwas decanted, concentrated, and the oily residue was subject to agradient column chromatography (EtOAc-Hex:from 1:20 to 1:6) yielding thetitle compound as an amber oil (2.39 g, 97%).

Step 3(S)-N-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide

To the solution of(S)-5-bromo-N-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)(oxido)phenyl-

-sulfanylidene]nicotinamide (1.9 g, 3.82 mmol) in anhydrous DMF (19 mL)under nitrogen atmosphere was added sequentially3-methyl-furan-2-carboxylic acid (3-ethynyl-phenyl)-amide (1.72 g),triethylamine (2.13 mL), bis(triphenylphosphine)palladium(II) dichloride(268 mg), and triphenylphosphine (25 mg). The reaction system was placedunder a N₂—H₂ (1:1) atmosphere and CuI (145 mg) was added in oneportion. After the reaction mixture was stirred and heated at 60° C. for1.5 hours, it was poured into saturated aqueous NaHCO₃. The aqueous wasextracted with EtOAc (1×), which was subsequently washed with aqueousNaHCO₃ (1×), brine (1×), and dried (anhydrous Na₂SO₄). The organic layerwas decanted, evaporated and wrapped with silica gel. Two times columnchromatography (EtOAc-Hex:from 1:4 to 1:2; and MeOH—CH₂Cl₂: 1:100) gavethe title compound as yellow foam (2.2 g, 90%).

Step 4(S)-N-[(3-hydroxypropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide

To the solution of(S)-N-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)(oxido)phenyl-

-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide(2.2 g, 3.43 mmol) in anhydrous THF (60 mL) at 0° C. was added dropwisetert-butylammonium fluoride (7.2 mL, 1 M in THF) and the reaction wasstirred at 0° C. for 1 hour. The yellow reaction solution was thenconcentrated at room temperature to give a red oil. The oily residue wasdiluted with EtOAc, which was washed with saturated aqueous NaHCO₃ (2×),brine (1×), and then dried (anhydrous Na₂SO₄). The organic layer wasdecanted, concentrated, and the resulting oily residue waschromatographed (MeOH—CH₂Cl₂: from 1:100 to 1:50) yielding the titlecompound as a clear oil which turned into white foam in-vacuo (1.72 g,95%).

EXAMPLE 507(S)-N-[(3-bromopropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide

N-[(3-hydroxypropyl)(oxido)phenyl-

-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide(1.71 g, 3.24 mmol) was dissolved in anhydrous CH₂Cl₂ (5 mL) and theresulting solution was cooled to 0° C. A solution of carbon tetrabromide(1.565 g ) in CH₂Cl₂ (3 mL) was added dropwise followed by a dropwiseaddition of a solution of triphenylphosphine (1.24 g) in CH₂Cl₂ (3 mL).The reaction was stirred at room temperature for 1.5 hours and thenpartitioned between saturated aqueous NaHCO₃ and dichloromethane. Theorganic layer was separated, washed with brine (1×), dried withanhydrous Na₂SO₄, and concentrated with silica gel under reducedpressure. A gradient column chromatography (acetone-hex: from 1:10 to1:4) rendered title compound as white solid in amount of 1.56 g (82%).

EXAMPLE 508(S)-N-[(3-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}propyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide

To the solution of N-[(3-bromopropyl)(oxido)phenyl-

-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide(450 mg, 0.76 mmol) in anhydrous DMF (5 mL) was added dropwise1-[2-(2-hydroxyethoxy)ethyl]piperazine. The resulting reaction solutionwas stirred and heated at 80° C. for 30 min. It was then partitionedbetween saturated aqueous NaHCO₃ and EtOAc. The EtOAc layer wasseparated and washed with brine (1×). The aqueous NaHCO₃ layer wasextracted with CHCl₃ (1×) and the extract was washed with brine (1×).The organic layers were combined and dried over anhydrous sodiumsulfate. The organic solution was decanted, concentrated, and wrappedwith silica gel. Column chromatography (MeOH-EtOAc from 1:10 to 1:6)rendered the title compound as white foam in amount of 500 mg (96%).

EXAMPLE 509

(S)-N-{[3-(diethylamino)propyl](oxido)phenyl--sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide

In a manner similar to that described for Example 508,N-[(3-bromopropyl)(oxido)phenyl-

-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamideand diethylamine were converted to the title compound.

EXAMPLE 510

(S)-N-[{3-[(2-hydroxyethyl)amino]propyl}(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide

In a manner similar to that described for Example 508,N-[(3-bromopropyl)(oxido)phenyl-

-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamideand 2-hydroxyethylamine were converted to the title compound.

EXAMPLE 511

N-{[3-(3-hydroxypyrrolidin-1-yl)propyl](oxido)phenyl--sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide

In a manner similar to that described for Example 508,N-[(3-bromopropyl)(oxido)phenyl-

-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamideand 3-hydroxypyrrolidine were converted to the title compound.

EXAMPLE 512

N-[{3-[(2,3-dihydroxypropyl)(methyl)amino]propyl}(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide

In a manner similar to that described for Example 508,N-[(3-bromopropyl)(oxido)phenyl-

-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamideand 3-methylamino-1,2-propanediol were converted to the title compound.

EXAMPLE 513

(S)-N-{[3-(1,1-dioxidothiomorpholin-4-yl)propyl](oxido)phenyl--sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide

In a manner similar to that described for Example 508,N-[(3-bromopropyl)(oxido)phenyl-

-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamideand thiomorpholine-1,1-dioxide were converted to the title compound.

EXAMPLE 514

(S)-N-[{3-[4-(2-hydroxyethyl)piperazin-1-yl]propyl}(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide

In a manner similar to that described for Example 508,N-[(3-bromopropyl)(oxido)phenyl-

-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamideand 1-piperazineethanol were converted to the title compound.

EXAMPLE 515

N-{[3-(3-fluoropiperidin-1-yl)propyl](oxido)phenyl-

-sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide

In a manner similar to that described for example 508,N-[(3-bromopropyl)(oxido)phenyl-

-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamideand 3-fluoropiperidine were converted to the title compound.

EXAMPLE 516

(S)-N-{[3-(3,3-difluoropiperidin-1-yl)propyl](oxido)phenyl--sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide

In a manner similar to that described for Example 508,N-[(3-bromopropyl)(oxido)phenyl-

-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamideand 3,3-difluoropiperidine were converted to the title compound.

EXAMPLE 517

(S)-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)-N-[(3-morpholin-4-ylpropyl)(oxido)phenyl--sulfanylidene]nicotinamide

In a manner similar to that described for Example 508,N-[(3-bromopropyl)(oxido)phenyl-

-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamideand morpholine were converted to the title compound.

EXAMPLE 518

5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)-N-[oxido(phenyl){3-[3-(trifluoromethyl)piperidin-1-yl]propyl}--sulfanylidene]nicotinamide

In a manner similar to that described for example 508,N-[(3-bromopropyl)(oxido)phenyl-

-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamideand 3-(trifluoromethyl)piperidine were converted to the title compound.

EXAMPLE 519

(S)-N-{[3-(4-hydroxypiperidin-1-yl)propyl](oxido)phenyl--sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide

In a manner similar to that described for Example 508,N-[(3-bromopropyl)(oxido)phenyl-

-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamideand 4-hydroxypiperidine were converted to the title compound.

EXAMPLE 520

(S)-N-[{3-[(2-hydroxyethyl)(methyl)amino]propyl}(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide

In a manner similar to that described for Example 508,N-[(3-bromopropyl)(oxido)phenyl-

-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamideand 2-methylaminoethanol were converted to the title compound.

EXAMPLE 521

5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)-N-[(3-{methyl[(2S,3R,4S,5R)-2,3,4,5,6-pentahydroxyhexyl]amino}propyl)(oxido)phenyl--sulfanylidene]nicotinamide

In a manner similar to that described for Example 508,N-[(3-bromopropyl)(oxido)phenyl-

-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamideand 1-deoxy-1-(methylamino)-D-galactitol were converted to the titlecompound.

EXAMPLE 522

(S)-N-[(3-azidopropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide

In a manner similar to that described for Example 508,N-[(3-bromopropyl)(oxido)phenyl-

-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamideand sodium azide were converted to the title compound.

EXAMPLE 523

(S)-N-[(3-aminopropyl)(oxido)phenyl-□⁴-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide

In a manner similar to that described for example 508,(S)-N-[(3-bromopropyl)(oxido)phenyl-

-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamideand ammonia were converted to the title compound.

EXAMPLE 524(S)-N-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)(oxido)phenyl--sulfanylidene]-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide

In a manner similar to that described in Example 506 (step 3),(S)-5-bromo-N-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)(oxido)phenyl-

-sulfanylidene]nicotinamide andN-(3-ethynylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide are convertedto the title compound.

EXAMPLE 525(S)-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N-[(3-hydroxypropyl)(oxido)phenyl-lambda--sulfanylidene]nicotinamide

In a manner similar to that described in Example 506 (step 4),(S)-N-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)(oxido)phenyl-

-sulfanylidene]-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamideis converted to the title compound.

EXAMPLE 526(S)-N-[(3-bromopropyl)(oxido)phenyl-4-sulfanylidene]-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide

In a manner similar to that described in Example 507,(S)-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N-[(3-hydroxypropyl)(oxido)phenyl-lambda-

-sulfanylidene]nicotinamide is converted to the title compound.

EXAMPLE 527

(S)-N-{[3-(diethylamino)propyl](oxido)phenyl--sulfanylidene}-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide

In a manner similar to that described for example 508,(S)-N-[(3-bromopropyl)(oxido)phenyl-4-sulfanylidene]-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamideand diethylamine were converted to the title compound.

EXAMPLE 528

(S)-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N-[{3-[(2-hydroxyethyl)amino]propyl}(oxido)phenyl--sulfanylidene]nicotinamide

In a manner similar to that described for example 508,(S)-N-[(3-bromopropyl)(oxido)phenyl-4-sulfanylidene]-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamideand hydroxyethylamine were converted to the title compound.

EXAMPLE 529

(S)-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N-[{3-[(2-hydroxyethyl)(methyl)amino]propyl}(oxido)phenyl--sulfanylidene]nicotinamide

In a manner similar to that described for example 508,(S)-N-[(3-bromopropyl)(oxido)phenyl-4-sulfanylidene]-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamideand 2-methylaminoethanol were converted to the title compound.

EXAMPLE 530

(S)-N-{[3-(dimethylamino)propyl](oxido)phenyl--sulfanylidene}-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide

In a manner similar to that described for example 508,(S)-N-[(3-bromopropyl)(oxido)phenyl-

-sulfanylidene]-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamideand dimethylamine were converted to the title compound.

EXAMPLE 531

(S)-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N-[(3-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}propyl)(oxido)phenyl--sulfanylidene]nicotinamide

In a manner similar to that described for example 508,(S)-N-[(3-bromopropyl)(oxido)phenyl-4-sulfanylidene]-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamideand 1-[2-(2-hydroxyethoxy)ethyl]piperazine were converted to the titlecompound.

EXAMPLE 532(S)-Ethyl(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)acetateStep 1 5-{3-[(3-Methyl-furan-2-carbonyl)-amino]-phenylethynyl}-nicotinicacid

In a manner similar to that described for Example 480 (step 1),3-methyl-furan-2-carboxylic acid (3-ethynyl-phenyl)-amide and 5-bromonicotinic acid were reacted to provide the title compound.

Step 2(S)-Ethyl(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)acetate

To a solution of ethyl(S)—(S-phenylsulfonimidoyl)acetate (139 mg, 0.61mmol) in anhydrous DMF (3 mL) at room temperature was added5-{3-[(3-Methyl-furan-2-carbonyl)-amino]-phenylethynyl}-nicotinic acid(233 mg), catalytic amount of 4-(dimethylamino)pyridine, andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (141 mg).The reaction mixture was stirred at room temperature for 30 min. Thereaction was then poured into aqueous HCl (0.5%) and extracted withEtOAc. After the aqueous layer was separated, solid sodium chloride wasadded and the resulting aqueous mixture was extracted again with EtOAc.The organic layers were combined, washed with brine (1×), saturatedaqueous NaHCO₃ (1×), then brine (1×), and finally dried with sodiumsulfate. The upper solution was decanted, concentrated, and the yellowoily residue was subject to a column chromatography (silica gel,gradient elution EtOAc-Hex from 1:5 to 1:1.5) to give the title compoundas a white foam (147 mg, 43

EXAMPLE 533N-{[2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl](oxido)phenyl--sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide

To the solution of(S)-ethyl(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)acetate(4.03 g, 7.26 mmol) in anhydrous THF (75 mL) was added dropwise3-pyrrolidinol (6.0 mL) and the resulting reaction solution was heatedat 65° C. for 5 hours. The reaction was then concentrated under reducedpressure and the yellow oily residue was partitioned between aqueousNH₄Cl and EtOAc. The organic layer was separated and washed sequentiallywith brine (1×), saturated aqueous NaHCO₃ (1×), brine (1×), and finallydried with anhydrous sodium sulfate overnight. The clear solution wasdecanted and concentrated. The oily residue was subject to multipletimes of column chromatography (eg. from CH₂Cl₂ to MeOH—CH₂Cl₂ 1:25 orfrom EtOAc-Hex 3:1 to MeOH-EtOAc 1:100) the title compound as white foam(2.35 g, 54%).

EXAMPLE 534N-[{2-[(2,3-dihydroxypropyl)(methyl)amino]-2-oxoethyl}(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide

To the solution of(S)-ethyl(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)acetate(3.5 g, 6.3 mmol) in anhydrous THF (50 mL) was added dropwise3-methylamino-1,2-propanediol (6.77 g) and the resulting reactionsolution was heated at 75° C. for 8.5 hours. The reaction was thenconcentrated under reduced pressure and the yellow oily residue waspartitioned between aqueous NH₄Cl and EtOAc. The organic layer wasseparated and washed with saturated aqueous NaHCO₃ (1×), brine (1×), anddried with sodium sulfate. The upper clear solution was decanted andevaporated, the resulting yellowish foamy residue was subjected to agradient column chromatography (from EtOAc-Hex 6:1 to MeOH-EtOAc 1:50)yielding the title compound as white foam in amount of 2.56 g (66%).

EXAMPLE 535(S)-N-{[2-(methylamino)-2-oxoethyl](oxido)phenyl--sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide

In a manner similar to that described in Example 534,(S)-Ethyl(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)acetateand methylamine were reacted to give the title compound.

EXAMPLE 536(S)-N-{[2-(4-hydroxypiperidin-1-yl)-2-oxoethyl](oxido)phenyl--sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide

In a manner similar to that described in Example 534,(S)-Ethyl(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)acetateand 4-hydroxypiperidine were reacted to give the title compound.

EXAMPLE 537(S)-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)-N-[oxido(2-oxo-2-pyrrolidin-1-ylethyl)phenyl--sulfanylidene]nicotinamide

In a manner similar to that described in Example 534,(S)-Ethyl(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)acetateand pyrrolidine were reacted to give the title compound.

EXAMPLE 538N-{[2-(3-hydroxypiperidin-1-yl)-2-oxoethyl](oxido)phenyl--sulfanylidene}-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide

In a manner similar to that described in Example 534,(S)-Ethyl(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)acetateand 3-hydroxypiperidine were reacted to give the title compound.

EXAMPLE 539 (S)-Ethyl1-[(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)acetyl]piperidine-3-carboxylate

In a manner similar to that described in Example 534,(S)-Ethyl(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)acetateand ethyl nipecotate were reacted to give the title compound.

EXAMPLE 540

(S)-Ethyl[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate

In a manner similar to that described in Example 532 (step 2),(S)-Ethyl(S)—(S-phenylsulfonimidoyl)acetate and5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinicacid were reacted to give the title compound.

EXAMPLE 541(S)-N-[{2-[(2-amino-2-oxoethyl)amino]-2-oxoethyl}(oxido)phenyl--sulfanylidene]-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide

In a manner similar to that described in Example 534,(S)-Ethyl[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetateand glycineamide were reacted to give the title compound.

EXAMPLE 542(S)-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N-{[2-(methylamino)-2-oxoethyl](oxido)phenyl--sulfanylidene}nicotinamide

In a manner similar to that described in Example 534,(S)-Ethyl[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetateand methylamine were reacted to give the title compound.

EXAMPLE 543(S)-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N-[{2-[(2-hydroxyethyl)amino]-2-oxoethyl}(oxido)phenyl--sulfanylidene]nicotinamide

In a manner similar to that described in Example 534,(S)-Ethyl[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetateand 2-hydroxyethylamine were reacted to give the title compound.

EXAMPLE 544(S)-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N-[{2-[(2-hydroxyethyl)(methyl)amino]-2-oxoethyl}(oxido)phenyl--sulfanylidene]nicotinamide

In a manner similar to that described in Example 534,(S)-Ethyl[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetateand 2-methylaminoethanol were reacted to give the title compound.

EXAMPLE 545N-[{2-[(2,3-dihydroxypropyl)amino]-2-oxoethyl}(oxido)phenyl--sulfanylidene]-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide

In a manner similar to that described in Example 534,(S)-Ethyl[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetateand 3-amino-1,2-propanediol were reacted to give the title compound.

EXAMPLE 546 (S)-Methyl5-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]pentanoateStep 1 (S)-Trimethyl{[methyl(oxido)phenyl-λ⁴-sulfanylidene]amino}silane

To a stirred solution of (S)-(+)-S-methyl-5-phenylsulphoximine (621 mg,4.0 mmol) in anhydrous acetonitrile (1 mL) at 70° C. was added(trimethylsilyl)diethylamine (1.37 mL, 7.0 mmol) dropwise. The reactionwas maintained at this temperature and stirred for 2 hours, at whichtime the TLC showed complete conversion of the starting material into ahigher R_(f) component. The reaction solution was concentrated underreduced pressure and dried in vacuo yielding brown oil, which was useddirectly in the next step without further purification.

Step 2(S)-9,9-dimethoxy-2,2-dimethyl-4-phenyl-10-oxa-λ⁴-thia-3-aza-2-silaundec-3-ene4-oxide

The brown oil, obtained from last step, was dissolved in 4 mL anhydrousTHF. After the solution was cooled to −78° C., n-butyllithium (1.64 mL,2.5 M solution in hexanes) was added dropwise. The resulting reactionmixture was stirred at −78° C. for 10 min, then at 0° C. for 20 min,followed by an addition of hexamethyl phosphoramide (1.32 mL). After thereaction was cooled back to −78° C., trimethyl 4-bromo-orthobutyrate(1.1 mL) was added dropwise. The reaction was stirred and itstemperature was allowed to rise to room temperature during 16 hours. Thereaction mixture was then diluted with ethyl ether (250 mL) and washedwith ice cold water (2×), brine (1×), and dried with anhydrous sodiumsulfate. The solution was decanted and concentrated giving a brown oilyresidue which was used directly for next step.

Step 3 (S)-[S-(5,5,5-trimethoxypentyl)sulfonimidoyl]benzene

To the solution of the oily residue, obtained in last step, in MeOH—H₂O(10:1, 2 mL) was added cesium fluoride (91.2 mg) and the resultingreaction mixture was heated at 50° C. for 2 hours. The reaction was thenconcentrated and the oily residue was partitioned between cold water andEtOAc. The organic layer was separated and washed with brine (1×). Afterit was dried with anhydrous sodium sulfate, it was concentrated for adirect use in next step.

Step 4 (S)-Methyl 5-(S-phenylsulfonimidoyl)pentanoate

The crude oil, obtained in last step, was dissolved in MeOH—H₂O (4:0.1,20 mL) and the resulting solution was cooled in an ice-bath. A catalyticamount of pyridinium toluene-4-sulfonate was added to the reaction andit was stirred at this temperature for 1 hour. The reaction was thenconcentrated at room temperature to remove most part of MeOH and theresidue was diluted with EtOAc. The EtOAc was washed with saturatedaqueous NaHCO₃ (2×), brine (1×), and dried with anhydrous sodiumsulfate. The organic was decanted, concentrated under reduced pressure,and wrapped with silica gel. A gradient chromatography (Et₂O-Hex from1:1 to Et₂O) rendered the title compound as clear oil in amount of 477mg (47% for total of 4 steps).

Step 5 (S)-Methyl5-{N-[(5-bromopyridin-3-yl)carbonyl]-S-phenylsulfonimidoyl}pentanoate

To the solution of (S)-Methyl 5-(S-phenylsulfonimidoyl)pentanoate (475mg, 1.86 mmol) in anhydrous DMF (6 mL) at room temperature undernitrogen atmosphere was added diisopropylethylamine (0.65 mL),5-bromonicotinic acid (0.38 g), and(benzotriazol-1-yloxy)-tris(dimethylamino)-phosphoniumhexafluorophosphate (0.81 g). The resulting reaction mixture was stirredfor about 15 min at room temperature and then poured into saturatedaqueous NaHCO₃. The aqueous was extracted with EtOAc (1×), which wasthen washed with saturated aqueous NaHCO₃ and brine (v:v 1:1, 2×), brine(1×), and dried with anhydrous sodium sulfate. The solution was decantedand concentrated with silica gel. A column chromatography (EtOAc-Hex1:2) rendered the title compound as slightly yellow colored solid inamount of (616 mg, 75%).

Step 6 (S)-Methyl5-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]pentanoate

To the flame-dried 100 mL round bottom flask containing (S)-Methyl5-{N-[(5-bromopyridin-3-yl)carbonyl]-S-phenylsulfonimidoyl}pentanoate(609 mg, 1.39 mmol),N-(3-ethynylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (0.50 g),triethylamine (0.77 mL), bis(triphenylphosphine)palladium(II) dichloride(97.3 mg), and triphenylphosphine (9.1 mg) under nitrogen/hydrogen (1:1)atmosphere at room temperature was added copper(I) iodide (52.8 mg). Theresulting reaction mixture was heated and stirred at 60° C. for 1 hour.It was then diluted with EtOAc, washed sequentially with saturatedaqueous NaHCO₃ (2×), brine (1×), and finally dried with anhydrous sodiumsulfate. The solution was decanted and concentrated with silica gel.Chromatography (EtOAc-Hex from 1:2 to 3:2) yielded the title compound aswhite foam in amount of (712 mg, 86%).

EXAMPLE 547N-[{5-[(2,3-dihydroxypropyl)(methyl)amino]-5-oxopentyl}(oxido)phenyl-λ⁴-sulfanylidene]-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide

To the solution of 3-methylamino-1,2-propanediol (180 mg) in anhydrousTHF was added (S)-Methyl5-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]pentanoate(100 mg, 0.17 mmol). The reaction solution was heated to 50° C. for 2hours and then the temperature was raised to 70° C. for 17 hours.Further 3-methylamino-1,2-propanediol (100 mg) was added, and thereaction was stirred and heated at 85° C. for an additional 24 hours.The reaction mixture was then partitioned between saturated aqueousNaHCO₃ and EtOAc. The organic layer was isolated and washed with brine(1×), dried (anhydrous Na₂SO₄) and concentrated. Upon a gradient columnchromatography (MeOH-EtOAc from 1:50 to 1:15) the title compound wasobtained as a clear oil (74 mg, 66%) which gave a white foamy solid uponstanding in vacuo.

EXAMPLE 548(S)-5-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]pentanoicacid

To the solution of (S)-Methyl5-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]pentanoate(120 mg, 0.2 mmol) in THF (4 mL) at 0° C. was added dropwise a solutionof aqueous NaOH (0.5 N, 2.0 mL). After the reaction mixture was stirredat 0° C. for 2 hours, 2 N HCl was carefully added to adjust the pH˜5followed by a partition between aqueous NH₄Cl and EtOAc. The EtOAc layerwas further washed with brine once and dried with anhydrous sodiumsulfate. The organic layer was decanted, concentrated and subject to agradient column chromatography (from EtOAc to MeOH-EtOAc 1:5) yieldingthe title compound as white foam in amount of (85 mg, 73%).

EXAMPLE 549(S)-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N-{[5-(hydroxyamino)-5-oxopentyl](oxido)phenyl-λ⁴-sulfanylidene}nicotinamide

At 0° C. to the solution of5-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]pentanoicacid (50 mg, 0.086 mmol) in DMF (1 mL) was added hydroxylaminehydrochloride (30 mg), 1-hydroxybenzotriazole hydrate (20 mg),(benzotriazol-1-yloxy)-tris(dimethylamino)-phosphoniumhexafluorophosphate (57 mg), and triethylamine (84 μL). The reactionmixture was stirred at this temperature for 30 min. The reaction wasthen poured into aqueous NH₄Cl and extracted with EtOAc. The organiclayer was isolated, washed further with brine once, and dried (anhydrousNa₂SO₄). A gradient column chromatography (MeOH—CH₂Cl₂ from 1:100 to1:5) gave the title compound as white foam (37 mg, 71%).

EXAMPLE 550 Methylrel-(2R,4S)-1-{3-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-R-phenylsulfonimidoyl]propyl}-4-hydroxypyrrolidine-2-carboxylate

The mixture ofN-[(3-bromopropyl)(oxido)phenyl-λ⁴-sulfanylidene]-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide(200 mg, 0.33 mmol), L-4-hydroxyproline methyl ester hydrochloride (126mg), and sodium bicarbonate (167 mg) in anhydrous acetonitrile (2 mL) ina seal tube was stirred and heated at 90° C. for 5 hours. After it wascooled to room temperature, the reaction was diluted with EtOAc. Theorganic was washed with saturated aqueous NaHCO₃ (2×), brine (1×), andthen dried with anhydrous sodium sulfate. The solution layer wasdecanted, concentrated, and the oily residual was chromatographed(EtOAc-Hex 1:1 to neat EtOAc) yielding the title compound as colorlessoil in amount of 128 mg (58%).

EXAMPLE 551(S)-Methyl({3-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]propyl}amino)acetate

In a manner similar to that described in Example 550,N-[(3-bromopropyl)(oxido)phenyl-λ⁴-sulfanylidene]-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamideand glycine methyl ester were reacted to give the title compound.

EXAMPLE 552 Methyl2-({3-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]propyl}amino)-3-hydroxypropanoate

In a manner similar to that described in Example 550,N-[(3-bromopropyl)(oxido)phenyl-λ⁴-sulfanylidene]-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamideand 2-amino-3-hydroxypropionic acid methyl ester were reacted to givethe title compound.

EXAMPLE 553 Ethyl1-{3-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]propyl}piperidine-3-carboxylate

In a manner similar to that described in Example 550,N-[(3-bromopropyl)(oxido)phenyl-λ⁴-sulfanylidene]-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamideand ethyl nipecotate were reacted to give the title compound.

EXAMPLE 554 Methyl2-({3-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]propyl}amino)-3-(1H-imidazol-4-yl)propanoate

In a manner similar to that described in Example 550,N-[(3-bromopropyl)(oxido)phenyl-λ⁴-sulfanylidene]-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamideand histidine methyl ester were reacted to give the title compound.

EXAMPLE 555rel-(2R,4S)-1-{3-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-R-phenylsulfonimidoyl]propyl}-4-hydroxypyrrolidine-2-carboxylicacid

Methylrel-(2R,4S)-1-{3-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-R-phenylsulfonimidoyl]propyl}-4-hydroxypyrrolidine-2-carboxylate(116 mg, 0.17 mmol) was dissolved in THF (3.5 mL) and the resultingsolution was cooled in an ice-bath. After aqueous NaOH (0.5 N, 1.75 mL)was dropwise added, the reaction was stirred at 0° C. for 30 min. Thereaction was then diluted with ice water followed by a pH adjustment to3˜4 with 2 N HCl. The reaction was further diluted with saturated brine,and then extracted with CHCl₃-iPrOH (5:1) (2×). The organic layers werecombined, dried (anhydrous Na₂SO₄), and then filtered through a plug ofcotton. The filtrate was concentrated and the residue waschromatographed (MeOH—CHCl₃ 1:10 to 1:4) yielding the title compound aswhite solid in amount of 108 mg (95%).

EXAMPLE 556({3-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]propyl}amino)aceticacid

In a manner similar to that described in Example 555,methyl({3-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]propyl}amino)acetatewas converted to the title compound.

EXAMPLE 5572-({3-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]propyl}amino)-3-hydroxypropanoicacid

In a manner similar to that described in Example 555, methyl2-({3-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]propyl}amino)-3-hydroxypropanoatewas converted to the title compound.

EXAMPLE 5581-{3-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]propyl}piperidine-3-carboxylicacid

In a manner similar to that described in Example 555, ethyl1-{3-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]propyl}piperidine-3-carboxylatewas converted to the title compound.

EXAMPLE 559(S)-Methyl{[3-(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)propyl]amino}acetate

In a manner similar to that described in Example 550,N-[(3-bromopropyl)(oxido)phenyl-λ⁴-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamideand glycine methyl ester are converted to the title compound.

EXAMPLE 560 methyl1-[3-(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)propyl]pyrrolidine-2-carboxylate

In a manner similar to that described in Example 550,N-[(3-bromopropyl)(oxido)phenyl-lambda˜4˜-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamideand 2-carboxymethyl pyrrolidine are converted to the title compound.

EXAMPLE 561 methyl1-[3-(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)propyl]pyrrolidine-3-carboxylate

In a manner similar to that described in Example 550,N-[(3-bromopropyl)(oxido)phenyl-λ⁴-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamideand 3-carboxymethyl pyrrolidine are converted to the title compound.

EXAMPLE 562 ethyl1-[3-(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)propyl]piperidine-3-carboxylate

In a manner similar to that described in Example 550,N-[(3-bromopropyl)(oxido)phenyl-λ⁴-sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamideand ethyl nipecotate are converted to the title compound.

EXAMPLE 563(S)-{[3-(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)propyl]amino}aceticacid

In a manner similar to that described in Example 555,methyl{[3-(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)propyl]amino}acetateis converted to the title compound.

EXAMPLE 5641-[3-(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)propyl]pyrrolidine-2-carboxylicacid

In a manner similar to that described in Example 555, methyl1-[3-(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)propyl]pyrrolidine-2-carboxylateis converted to the title compound.

EXAMPLE 5651-[3-(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)propyl]pyrrolidine-3-carboxylicacid

In a manner similar to that described in Example 555, methyl1-[3-(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)propyl]pyrrolidine-3-carboxylateis converted to the title compound.

EXAMPLE 5661-[3-(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)propyl]piperidine-3-carboxylicacid

In a manner similar to that described in Example 555, ethyl1-[3-(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)propyl]piperidine-3-carboxylateis converted to the title compound.

EXAMPLE 567methyl{3-[N-({6-amino-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]phenyl}acetateStep 1 methyl6-amino-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinate

A mixture of methyl 6-amino-5-iodonicotinate (111 mg, 0.40 mmol),N-(3-ethynylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (144 mg, 0.60mmol), triethylamine (0.167 ml, 1.2 mmol),dichlorobis(triphenylphosphine)palladium(II) (23 mg, 0.032 mmol) andtriphenylphosphine (5.2 mg, 0.020 mmol) in 3.2 ml DMF at roomtemperature was degassed using vacuum and a balloon of H₂, thencopper(I) iodide (3.8 mg, 0.020 mmol) added. The reaction was heated at60□ C. for 1 hour 40 minutes, then partitioned between EtOAc and dilutebrine. The EtOAc layer was dried with anhydrous Na₂SO₄ and rotaryevaporated. The solid was recrystallized from EtOAc/hexane to give thetitle compound as a yellow-tan solid (122 mg, 78%).

Step 26-amino-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinicacid

A solution of methyl6-amino-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinate(51 mg, 0.13 mmol) and KOH (37 mg, 0.65 mmol) in 4.0 ml MeOH:H₂O (3:1)was heated at 65□C. for 1 hour 40 minutes. The pH of the mixture wasadjusted to pH 4 using 10% HCl, brine added, and the aqueous extractedwith EtOAc. The combined EtOAc layers were dried with anhydrous Na₂SO₄and rotary evaporated. The light yellow solid was triturated with hotEtOAc to give the title compound as an off-white solid (41 mg, 84%).

Step 3methyl{3-[N-({6-amino-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]phenyl}acetate

In a manner similar to that described in Example 496 (step 5),6-amino-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinicacid andmethyl{3-[S-methyl-N-(trifluoroacetyl)sulfonimidoyl]phenyl}acetate werereacted to give the title compound.

The present invention is not to be limited in scope by the exemplifiedembodiments which are intended as illustrations of single aspects of theinvention only. Indeed, various modifications of the invention inaddition to those described herein will become apparent to those skilledin the art from the foregoing description.

For example, the novel compounds of this invention include any compoundwhich is a substituted aroyl sulfoximine compound which binds to thetyrosine kinase receptor wherein said substituted aryl moiety may berepresented by formula IV below:

or said substituted aryl moiety may be represented by formula V below

wherein B¹, R¹² and R¹³ are selected from the group consisting ofhalogen, nitro, hydroxy, hydrocarbyl, substituted hydrocarbyl, amide,thioamide, amine, thioether and cyano or said novel sulfoximine may berepresented by formula VI below

wherein Z is said substituted aroyl group and E¹ and E² are selectedfrom the group consisting of halogen, nitro, hydroxy, hydrocarbyl,substituted hydrocarbyl, amide, thioamide, amine, thioether and cyano.

Such modifications are intended to fall within the scope of the appendedclaims.

All references cited herein are hereby incorporated by reference intheir entirety.

In particular, the compounds of the present invention may be prepared bymethods that are analogous to the methods disclosed in such references,with one of skill in the art varying the reactants to achieve thedesired compounds. Also, the compounds of the present invention may betested by the various in-vitro and in-vivo assays disclosed in suchreferences to demonstrate the claimed utilities.

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. However, it is apparent for one of ordinaryskill in the art that further compounds with the desired pharmacologicalproperties can be prepared in an analogous manner, and that thedisclosed compounds can also be obtained from different startingcompounds via different chemical reactions. Similarly, differentpharmaceutical compositions may be prepared and used with substantiallythe same result. Thus, however detailed the foregoing may appear intext, it should not be construed as limiting the overall scope hereof;rather, the ambit of the present invention is to be governed only by thelawful construction of the appended claims.

1. A compound represented by the general formula I:

Wherein: X is CR⁴ or N; Y is CR¹ or N; R¹ is selected from the groupconsisting of hydrogen, alkyl, halogen, OR⁴, CN, NO₂, COR⁴,(CH₂)_(a)OR⁴, (CH₂)_(a)N(R⁴)₂, C(O)N(R⁴)₂ and N(R⁴)₂; R² is selectedfrom the group consisting of hydrogen, halogen, alkyl, OR⁴, CN, NO₂,SO₂N(R⁴)₂, COR⁴, (CH₂)_(a)OR⁴, (CH₂)_(a)N(R⁴)₂, C(O)N(R⁴)₂, N(R⁴)₂ andN(R⁶)(CR⁷R⁸)_(a)R¹⁰; R³ is selected from the group consisting ofhydrogen, halogen, alkyl, OR⁴, CN, NO₂, SO₂N(R⁴)₂, COR⁴, (CH₂)_(a)OR⁴,(CH₂)_(a)N(R⁴)₂, C(O)N(R⁴)₂, N(R⁴)₂ and N(R⁶)(CR⁷R⁸)_(a)R¹⁰; R⁴ ishydrogen or C₁ to C₄ alkyl; A is selected from the group consisting ofC≡C, CH═CH, CH₂CH₂, CH₂O, CF₂O, OCH₂, OCF₂, N(R⁴), C(O), S(O)_(e),NR⁷C(O), C(O)NR⁷ and N(R⁷)C(O)NR⁷; B is selected from the groupconsisting of hydrogen, alkyl and alkyloxyalkyl or B may be a 5 or 6membered carbocyclic aryl or heterocyclic aryl group; E is a 5 or 6membered carbocyclic aryl or heterocyclic aryl group; E′ is selectedfrom the group consisting of alkyl, CF₃, (CR⁷R⁸)_(a)C(O)OR¹⁰,(CR⁷R⁸)_(a)C(O)N(R¹⁰)₂, (CR⁷R⁸)_(a)C(O)N(OR¹⁰)(R¹⁰), (CR⁷R⁸)_(a)(OR¹⁰),(CR⁷R⁸)_(a)N(R¹⁰)₂, and (CR⁷R⁸)_(a)R¹⁰; wherein R⁷ and R⁸ are selectedfrom the group consisting of H, halogen, hydroxyl, and alkyl or CR⁷R⁸may represent a carbocyclic ring of from 3 to 6 carbons; and R¹⁰ isselected from the group consisting of hydrogen, halogen, alkyl,hydroxyl, hydroxymethyl, carbocyclic aryl, heterocyclic aryl,(CR⁷R⁸)_(a)C(O)OR⁶, (CR⁷R⁸)_(a)C(O)R₆, (CR⁷R⁸)_(a)C(O)N(R⁶)₂,(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶), (CR⁷R⁸)_(a)(OR⁶), (CR⁷R⁸)_(a)N(R⁶)₂ and(CR⁷R⁸)_(a)R⁶, wherein R⁶ is selected from the group consisting ofhydrogen, carboalkyl, alkylamine, alkylhydroxy, and alkyloxyalkyl or R⁶is a 5 or 6 membered carbocyclic or heterocyclic group; wherein R⁶ isselected from the group consisting of hydrogen, alkyl, carboalkyl,alkylamine, alkylhydroxy and alkyloxyalkyl or R⁶ is a 5 or 6 memberedcarbocyclic or heterocyclic group; a is 0 or an integer of from 1 to 5;b is an integer of from 2 to 5; c is 0 or an integer of from 1 to 4; dis 0 or an integer of from 1 to 5; e is 0 or an integer of from 1 to 2and further including prodrugs, pharmaceutically acceptable salts,racemic mixtures and enantiomers of said compound.
 2. The compound ofclaim 1 wherein B is a carbocyclic aryl or heterocyclic aryl representedby formula II below:

wherein said carbocyclic aryl and heterocyclic aryl groups are selectedfrom the group consisting of:

wherein R is selected from the group consisting of halogen, alkyl, CF₃,OCF₃, OCF₂H, CH₂CN, CN, SR⁶, OP(O)(OR⁶)₂, OCH₂O, HC═N—NH, N═CH—S,(CR⁷R⁸)_(a)C(O)R⁶, O(CR⁷R⁸)_(a)C(O)R⁶, N(R⁶)(CR⁷R⁸)_(a)C(O)R⁶,C(O)(CR⁷R⁸)_(a)C(O)R⁶, S(O)_(e)(CR⁷R⁸)_(a)C(O)R⁶, (CR⁷R⁸)_(a)C(O)OR⁶,O(CR⁷R⁸)_(a)C(O)OR⁶, N(R⁶)(CR⁷R⁸)_(a)C(O)OR⁶, C(O)(CR⁷R⁸)_(a)C(O)OR⁶,S(O)_(e)(CR⁷R⁸)_(a)C(O)OR⁶, O(CR⁷R⁸)_(a)C(O)N(R⁶)₂,N(R⁶)(CR⁷R⁸)_(a)C(O)N(R⁶)₂, C(O)(CR⁷R⁸)_(a)C(O)N(R⁶)₂,S(O)_(e)(CR⁷R⁸)_(a)C(O)N(R⁶)₂, (CR⁷R⁸)_(a)N(R⁶)C(O)N(R⁶)₂,O(CR⁷R⁸)_(b)N(R⁶)C(O)N(R⁶)₂, N(R⁶)(CR⁷R⁸)_(b)N(R⁶)C(O)N(R⁶)₂,C(O)(CR⁷R⁸)_(a)N(R⁶)C(O)N(R⁶)₂, S(O)_(e)(CR⁷R⁸)_(a)N(R⁶)C(O)N(R⁶)₂,(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶), O(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶),N(R⁶)(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶), C(O)(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶),S(O)_(e)(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶), (CR⁷R⁸)_(a)(OR⁶), O(CR⁷R⁸)_(a)(OR⁶),N(R⁶)(CR⁷R⁸)_(a)(OR⁶), C(O)(CR⁷R⁸)_(a)(OR⁶), S(O)_(e)(CR⁷R⁸)_(a)(OR⁶),(CR⁷R⁸)_(a)N(R⁶)₂, O(CR⁷R⁸)_(b)N(R⁶)₂, N(R⁶)(CR⁷R⁸)_(b)N(R⁶)₂,C(O)(CR⁷R⁸)_(a)N(R⁶)₂, S(O)_(e)(CR⁷R⁸)_(a)N(R⁶)₂, (CR⁷R⁸)_(a)R⁶,O(CR⁷R⁸)_(a)R⁶, N(R⁶)(CR⁷R⁸)_(a)R⁶, C(O)(CR⁷R⁸)_(a)R⁶ and,S(O)_(e)(CR⁷R⁸)_(a)R⁶ wherein R⁶ is selected from the group consistingof hydrogen, alkyl, carboalkyl, alkylamine, alkylhydroxy andalkyloxyalkyl or R⁶ is a 5 or 6 membered carbocyclic or heterocyclicgroup.
 3. The compound of claim 2 wherein R⁶ is selected from the groupconsisting of hydrogen, alkyl, dilower alkyl amine or a heterocyclicgroup represented by the list below or N(R⁶)₂ may represent a 3 to 7membered heterocyclic group,

wherein R⁵ is hydrogen, halogen, simple alkyl, CF₃, hydroxyl, OR⁷,N(R⁷)₂ or NO2.
 4. The compound of claim 2 wherein R⁶ is selected fromthe group consisting of hydrogen, alkyl, dilower alkyl amine,3-fluoropyrrolidinyl, 3-fluoropiperidinyl, 2-pyridinyl, 3-pyridinyl,4-pyridinyl, 3-pyrrolinyl, pyrrolidinyl, methyl isonipecotate,N-(2-methoxyethyl)-N-methylamyl, 1,2,3,6-tetrahydropyridinyl,morpholinyl, hexamethyleneiminyl, piperazinyl-2-one, piperazinyl,N-(2-methoxyethyl)ethylaminyl, thiomorpholinyl, heptamethyleneiminyl,1-piperazinylcarboxaldehyde,2,3,6,7-tetrahydro-(1H)-1,4-diazepinyl-5(4H)-one,N-methylhomopiperazinyl, (3-dimethylamino)pyrrolidinyl,N-(2-methoxyethyl)-N-propylaminyl, isoindolinyl, nipecotamidinyl,isonipecotamidinyl, 1-acetylpiperazinyl, 3-acetamidopyrrolidinyl,trans-decahydroisoquinolinyl, cis-decahydroisoquinolinyl,N-acetylhomopiperazinyl, 3-(diethylamino)pyrrolidinyl,1,4-dioxa-8-azaspiro[4.5]decaninyl, 1-(2-methoxyethyl)-piperazinyl,2-pyrrolidin-3-ylpyridinyl, 4-pyrrolidin-3-ylpyridinyl,3-(methylsulfonyl)pyrrolidinyl, 3-picolylmethylaminyl,2-(2-methylaminoethyl)pyridinyl, 1-(2-pyrimidyl)-piperazinyl,1-(2-pyrazinyl)-piperazinyl, 2-methylaminomethyl-1,3-dioxolane,2-(N-methyl-2-aminoethyl)-1,3-dioxolane,3-(N-acetyl-N-methylamino)pyrrolidinyl, 2-methoxyethylaminyl,tetrahydrofurfurylaminyl, 4-aminotetrahydropyran,2-amino-1-methoxybutane, 2-methoxyisopropylaminyl,1-(3-aminopropyl)imidazole, histamyl, N,N-diisopropylethylenediaminyl,1-benzyl-3-aminopyrrolidyl 2-(aminomethyl)-5-methylpyrazinyl,2,2-dimethyl-1,3-dioxolane-4-methanaminyl,(R)-3-amino-1-N—BOC-pyrrolidinyl,4-amino-1,2,2,6,6-pentamethylpiperidinyl, 4-aminomethyltetrahydropyranand ethanolamine.
 5. The compound of claim 2 wherein E is a 5 or 6membered carbocyclic aryl or heterocyclic aryl represented by formulaIII below:

wherein said carbocyclic aryl and heterocyclic aryl is selected from thegroup consisting of:


6. A compound of claim 3 wherein A is ≡.
 7. A compound of claim 6wherein


8. A compound of claim 6 wherein B is


9. A compound of claim 6 wherein R² is NH₂.
 10. A compound of claim 6wherein R³ is NH₂.
 11. A compound of claim 8 wherein


12. A compound of claim 6 wherein B is


13. A compound of claim 6 wherein B is


14. A compound of claim 12 wherein R² is NH₂.
 15. A compound of claim 12wherein R³ is NH₂.
 16. A compound of claim 13 wherein R² is NH₂.
 17. Acompound of claim 13 wherein R³ is NH₂.
 18. A compound of claim 12wherein


19. A compound of claim 13 wherein


20. A compound of claim 14 wherein


21. A compound of claim 15 wherein


22. A compound of claim 16 wherein


23. A compound of claim 17 wherein


24. A compound of claim 18 wherein R selected from the group consistingof halogen, alkyl, CF₃, OCF₃, OCF₂H, CH₂CN, CN, S(O)_(e)R⁶, SO₂N(R⁶)₂,OP(O)(OR⁶)₂, OCH₂O, HC═N—NH, N═CH—S, N═N—NH, (CR⁷R⁸)C(O)R⁶,O(CR⁷R⁸)_(a)C(O)R⁶, N(R⁶)(CR⁷R⁸)_(a)C(O)R⁶, C(O)(CR⁷R⁸)_(a)C(O)R⁶,S(O)_(e)(CR⁷R⁸)_(a)C(O)R⁶, (CR⁷R⁸)_(a)C(O)OR⁶, O(CR⁷R⁸)_(a)C(O)OR⁶,N(R⁶)(CR⁷R⁸)_(a)C(O)OR⁶, C(O)(CR⁷R⁸)_(a)C(O)OR⁶,S(O)_(e)(CR⁷R⁸)_(a)C(O)OR⁶, (CR⁷R⁸)_(a)C(O)N(R⁶)₂,O(CR⁷R⁸)_(a)C(O)N(R⁶)₂, N(R⁶)(CR⁷R⁸)_(a)C(O)N(R⁶)₂,C(O)(CR⁷R⁸)_(a)C(O)N(R⁶)₂, S(O)_(e)(CR⁷R⁸)_(a)C(O)N(R⁶)₂,(CR⁷R⁸)_(a)N(R⁶)C(O)N(R⁶)₂, O(CR⁷R⁸)_(b)N(R⁶)C(O)N(R⁶)₂,N(R⁶)(CR⁷R⁸)_(b)N(R⁶)C(O)N(R⁶)₂, C(O)(CR⁷R⁸)_(a)N(R⁶)C(O)N(R⁶)₂,S(O)_(e)(CR⁷R⁸)_(a)N(R⁶)C(O)N(R⁶)₂, (CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶),O(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶), N(R⁶)(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶),C(O)(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶), S(O)_(e)(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶),(CR⁷R⁸)_(a)(OR⁶), O(CR⁷R⁸) (OR⁶), N(R⁶)(CR⁷R⁸) (OR⁶),C(O)(CR⁷R⁸)_(a)(OR⁶), S(O)_(e)(CR⁷R⁸)_(a)(OR⁶), (CR⁷R⁸)_(a)N(R⁶)₂,O(CR⁷R⁸)_(b)N(R⁶)₂, N(R⁶)(CR⁷R⁸)_(b)N(R⁶)₂, C(O)(CR⁷R⁸)_(a)N(R⁶)₂,S(O)_(e)(CR⁷R⁸)_(a)N(R⁶)₂, (CR⁷R⁸)_(a)R⁶, O(CR⁷R⁸)_(a)R⁶,N(R⁶)(CR⁷R⁸)_(a)R⁶, C(O)(CR⁷R⁸)_(a)R⁶ and S(O)_(e)(CR⁷R⁸)_(a)R⁶.
 25. Acompound of claim 19 wherein R is selected from the group consisting ofhalogen, alkyl, CF₃, OCF₃, OCF₂H, CH₂CN, CN, S(O)_(e)R⁶, SO₂N(R⁶)₂,OP(O)(OR⁶)₂, OCH₂O, HC═N—NH, N═CH—S, N═N—NH, (CR⁷R⁸)_(a)C(O)R⁶,O(CR⁷R⁸)_(a)C(O)R⁶, N(R⁶)(CR⁷R⁸)_(a)C(O)R⁶, C(O)(CR⁷R⁸)_(a)C(O)R⁶,S(O)_(e)(CR⁷R⁸)_(a)C(O)R⁶, (CR⁷R⁸)_(a)C(O)OR⁶, O(CR⁷R⁸)_(a)C(O)OR⁶,N(R⁶)(CR⁷R⁸)_(a)C(O)OR⁶, C(O)(CR⁷R⁸)_(a)C(O)OR⁶,S(O)_(e)(CR⁷R⁸)_(a)C(O)OR⁶, (CR⁷R⁸)_(a)C(O)N(R⁶)₂,O(CR⁷R⁸)_(a)C(O)N(R⁶)₂, N(R⁶)(CR⁷R⁸)_(a)C(O)N(R⁶)₂,C(O)(CR⁷R⁸)_(a)C(O)N(R⁶)₂, S(O)_(e)(CR⁷R⁸)_(a)C(O)N(R⁶)₂,(CR⁷R⁸)_(a)N(R⁶)C(O)N(R⁶)₂, O(CR⁷R⁸)_(b)N(R⁶)C(O)N(R⁶)₂,N(R⁶)(CR⁷R⁸)_(b)N(R⁶)C(O)N(R⁶)₂, C(O)(CR⁷R⁸)_(a)N(R⁶)C(O)N(R⁶)₂,S(O)_(e)(CR⁷R⁸)_(a)N(R⁶)C(O)N(R⁶)₂, (CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶),O(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶), N(R⁶)(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶),C(O)(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶), S(O)_(e)(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶),(CR⁷R⁸)_(a)(OR⁶), O(CR⁷R⁸)_(a)(OR⁶), N(R⁶)(CR⁷R⁸)_(a)(OR⁶),C(O)(CR⁷R⁸)_(a)(OR⁶), S(O)_(e)(CR⁷R⁸)_(a)(OR⁶), (CR⁷R⁸)_(a)N(R⁶)₂,O(CR⁷R⁸)_(b)N(R⁶)₂, N(R⁶)(CR⁷R⁸)_(b)N(R⁶)₂, C(O)(CR⁷R⁸)_(a)N(R⁶)₂,S(O)_(e)(CR⁷R⁸)_(a)N(R⁶)₂, (CR⁷R⁸)_(a)R⁶, O(CR⁷R⁸)_(a)R⁶,N(R⁶)(CR⁷R⁸)_(a)R⁶, C(O)(CR⁷R⁸)_(a)R⁶ and S(O)_(e)(CR⁷R⁸)_(a)R⁶.
 26. Acompound of claim 20 wherein R is selected from the group consisting ofhalogen, alkyl, CF₃, OCF₃, OCF₂H, CH₂CN, CN, S(O)_(e)R⁶, SO₂N(R⁶)₂,OP(O)(OR⁶)₂, OCH₂O, HC═N—NH, N═CH—S, N═N—NH, (CR⁷R⁸)_(a)C(O)R⁶,O(CR⁷R⁸)_(a)C(O)R⁶, N(R⁶)(CR⁷R⁸)_(a)C(O)R⁶, C(O)(CR⁷R⁸)_(a)C(O)R⁶,S(O)_(e)(CR⁷R⁸)_(a)C(O)R⁶, (CR⁷R⁸)_(a)C(O)OR⁶, O(CR⁷R⁸)_(a)C(O)OR⁶,N(R⁶)(CR⁷R⁸)_(a)C(O)OR⁶, C(O)(CR⁷R⁸)_(a)C(O)OR⁶,S(O)_(e)(CR⁷R⁸)_(a)C(O)OR⁶, (CR⁷R⁸)_(a)C(O)N(R⁶)₂,O(CR⁷R⁸)_(a)C(O)N(R⁶)₂, N(R⁶)(CR⁷R⁸)_(a)C(O)N(R⁶)₂,C(O)(CR⁷R⁸)_(a)C(O)N(R⁶)₂, S(O)_(e)(CR⁷R⁸)_(a)C(O)N(R⁶)₂,(CR⁷R⁸)_(a)N(R⁶)C(O)N(R⁶)₂, O(CR⁷R⁸)_(b)N(R⁶)C(O)N(R⁶)₂,N(R⁶)(CR⁷R⁸)_(b)N(R⁶)C(O)N(R⁶)₂, C(O)(CR⁷R⁸)_(a)N(R⁶)C(O)N(R⁶)₂,S(O)_(e)(CR⁷R⁸)_(a)N(R⁶)C(O)N(R⁶)₂, (CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶),O(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶), N(R⁶)(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶),C(O)(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶), S(O)_(e)(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶),(CR⁷R⁸)_(a)(OR⁶), O(CR⁷R⁸)_(a)(OR⁶), N(R⁶)(CR⁷R⁸)_(a)(OR⁶),C(O)(CR⁷R⁸)_(a)(OR⁶), S(O)_(e)(CR⁷R⁸)_(a)(OR⁶), (CR⁷R⁸)_(a)N(R⁶)₂,O(CR⁷R⁸)_(b)N(R⁶)₂, N(R⁶)(CR⁷R⁸)_(b)N(R⁶)₂, C(O)(CR⁷R⁸)_(a)N(R⁶)₂,S(O)_(e)(CR⁷R⁸)_(a)N(R⁶)₂, (CR⁷R⁸)_(a)R⁶, O(CR⁷R⁸)_(a)R⁶,N(R⁶)(CR⁷R⁸)_(a)R⁶, C(O)(CR⁷R⁸)_(a)R⁶ and S(O)_(e)(CR⁷R⁸)_(a)R⁶.
 27. Acompound of claim 21 wherein R is selected from the group consisting ofhalogen, alkyl, CF₃, OCF₃, OCF₂H, CH₂CN, CN, S(O)_(e)R⁶, SO₂N(R⁶)₂,OP(O)(OR⁶)₂, OCH₂O, HC═N—NH, N═CH—S, N═N—NH, (CR⁷R⁸)_(a)C(O)R⁶,O(CR⁷R⁸)_(a)C(O)R⁶, N(R⁶)(CR⁷R⁸)_(a)C(O)R⁶, C(O)(CR⁷R⁸)_(a)C(O)R⁶,S(O)_(e)(CR⁷R⁸)_(a)C(O)R⁶, (CR⁷R⁸)_(a)C(O)OR⁶, O(CR⁷R⁸)_(a)C(O)OR⁶,N(R⁶)(CR⁷R⁸)_(a)C(O)OR⁶, C(O)(CR⁷R⁸)_(a)C(O)OR⁶,S(O)_(e)(CR⁷R⁸)_(a)C(O)OR⁶, (CR⁷R⁸)_(a)C(O)N(R⁶)₂,O(CR⁷R⁸)_(a)C(O)N(R⁶)₂, N(R⁶)(CR⁷R⁸)_(a)C(O)N(R⁶)₂,C(O)(CR⁷R⁸)_(a)C(O)N(R⁶)₂, S(O)_(e)(CR⁷R⁸)_(a)C(O)N(R⁶)₂,(CR⁷R⁸)_(a)N(R⁶)C(O)N(R⁶)₂, O(CR⁷R⁸)_(b)N(R⁶)C(O)N(R⁶)₂,N(R⁶)(CR⁷R⁸)_(b)N(R⁶)C(O)N(R⁶)₂, C(O)(CR⁷R⁸)_(a)N(R⁶)C(O)N(R⁶)₂,S(O)_(e)(CR⁷R⁸)_(a)N(R⁶)C(O)N(R⁶)₂, (CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶),O(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶), N(R⁶)(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶),C(O)(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶), S(O)_(e)(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶),(CR⁷R⁸)_(a)(OR⁶), O(CR⁷R⁸)_(a)(OR⁶), N(R⁶)(CR⁷R⁸)_(a)(OR⁶),C(O)(CR⁷R⁸)_(a)(OR⁶), S(O)_(e)(CR⁷R⁸)_(a)(OR⁶), (CR⁷R⁸)_(a)N(R⁶)₂,O(CR⁷R⁸)_(b)N(R⁶)₂, N(R⁶)(CR⁷R⁸)_(b)N(R⁶)₂, C(O)(CR⁷R⁸)_(a)N(R⁶)₂,S(O)_(e)(CR⁷R⁸)_(a)N(R⁶)₂, (CR⁷R⁸)_(a)R⁶, O(CR⁷R⁸)_(a)R⁶,N(R⁶)(CR⁷R⁸)_(a)R⁶, C(O)(CR⁷R⁸)_(a)R⁶ and S(O)_(e)(CR⁷R⁸)_(a)R⁶.
 28. Acompound of claim 22 wherein R is selected from the group consisting ofhalogen, alkyl, CF₃, OCF₃, OCF₂H, CH₂CN, CN, S(O)_(e)R⁶, SO₂N(R⁶)₂,OP(O)(OR⁶)₂, OCH₂O, HC═N—NH, N═CH—S, N═N—NH, (CR⁷R⁸)_(a)C(O)R⁶,O(CR⁷R⁸)_(a)C(O)R⁶, N(R⁶)(CR⁷R⁸)_(a)C(O)R⁶, C(O)(CR⁷R⁸)_(a)C(O)R⁶,S(O)_(e)(CR⁷R⁸)_(a)C(O)R⁶, (CR⁷R⁸)_(a)C(O)OR⁶, O(CR⁷R⁸)_(a)C(O)OR⁶,N(R⁶)(CR⁷R⁸)_(a)C(O)OR⁶, C(O)(CR⁷R⁸)_(a)C(O)OR⁶,S(O)_(e)(CR⁷R⁸)_(a)C(O)OR⁶, (CR⁷R⁸)_(a)C(O)N(R⁶)₂,O(CR⁷R⁸)_(a)C(O)N(R⁶)₂, N(R⁶)(CR⁷R⁸)_(a)C(O)N(R⁶)₂,C(O)(CR⁷R⁸)_(a)C(O)N(R⁶)₂, S(O)_(e)(CR⁷R⁸)_(a)C(O)N(R⁶)₂,(CR⁷R⁸)_(a)N(R⁶)C(O)N(R⁶)₂, O(CR⁷R⁸)_(b)N(R⁶)C(O)N(R⁶)₂,N(R⁶)(CR⁷R⁸)_(b)N(R⁶)C(O)N(R⁶)₂, C(O)(CR⁷R⁸)_(a)N(R⁶)C(O)N(R⁶)₂,S(O)_(e)(CR⁷R⁸)_(a)N(R⁶)C(O)N(R⁶)₂, (CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶),O(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶), N(R⁶)(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶),C(O)(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶), S(O)_(e)(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶),(CR⁷R⁸)_(a)(OR⁶), O(CR⁷R⁸)_(a)(OR⁶), N(R⁶)(CR⁷R⁸)_(a)(OR⁶),C(O)(CR⁷R⁸)_(a)(OR⁶), S(O)_(e)(CR⁷R⁸)_(a)(OR⁶), (CR⁷R⁸)_(a)N(R⁶)₂,O(CR⁷R⁸)_(b)N(R⁶)₂, N(R⁶)(CR⁷R⁸)_(b)N(R⁶)₂, C(O)(CR⁷R⁸)_(a)N(R⁶)₂,S(O)_(e)(CR⁷R⁸)_(a)N(R⁶)₂, (CR⁷R⁸)_(a)R⁶, O(CR⁷R⁸)_(a)R⁶,N(R⁶)(CR⁷R⁸)_(a)R⁶, C(O)(CR⁷R⁸)_(a)R⁶ and S(O)_(e)(CR⁷R⁸)_(a)R⁶.
 29. Acompound of claim 23 wherein R is selected from the group consisting ofhalogen, alkyl, CF₃, OCF₃, OCF₂H, CH₂CN, CN, S(O)_(e)R⁶, SO₂N(R⁶)₂,OP(O)(OR⁶)₂, OCH₂O, HC═N—NH, N═CH—S, N═N—NH, (CR⁷R⁸)_(a)C(O)R⁶,O(CR⁷R⁸)_(a)C(O)R⁶, N(R⁶)(CR⁷R⁸)_(a)C(O)R⁶, C(O)(CR⁷R⁸)_(a)C(O)R⁶,S(O)_(e)(CR⁷R⁸)_(a)C(O)R⁶, (CR⁷R⁸)_(a)C(O)OR⁶, O(CR⁷R⁸)_(a)C(O)OR⁶,N(R⁶)(CR⁷R⁸)_(a)C(O)OR⁶, C(O)(CR⁷R⁸)_(a)C(O)OR⁶,S(O)_(e)(CR⁷R⁸)_(a)C(O)OR⁶, (CR⁷R⁸)_(a)C(O)N(R⁶)₂,O(CR⁷R⁸)_(a)C(O)N(R⁶)₂, N(R⁶)(CR⁷R⁸)_(a)C(O)N(R⁶)₂,C(O)(CR⁷R⁸)_(a)C(O)N(R⁶)₂, S(O)_(e)(CR⁷R⁸)_(a)C(O)N(R⁶)₂,(CR⁷R⁸)_(a)N(R⁶)C(O)N(R⁶)₂, O(CR⁷R⁸)_(b)N(R⁶)C(O)N(R⁶)₂,N(R⁶)(CR⁷R⁸)_(b)N(R⁶)C(O)N(R⁶)₂, C(O)(CR⁷R⁸)_(a)N(R⁶)C(O)N(R⁶)₂,S(O)_(e)(CR⁷R⁸)_(a)N(R⁶)C(O)N(R⁶)₂, (CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶),O(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶), N(R⁶)(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶),C(O)(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶), S(O)_(e)(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶),(CR⁷R⁸)_(a)(OR⁶), O(CR⁷R⁸)_(a)(OR⁶), N(R⁶)(CR⁷R⁸)(OR⁶),C(O)(CR⁷R⁸)_(a)(OR⁶), S(O)_(e)(CR⁷R⁸)_(a)(OR⁶), (CR⁷R⁸)_(a)N(R⁶)₂,O(CR⁷R⁸)_(b)N(R⁶)₂, N(R⁶)(CR⁷R⁸)_(b)N(R⁶)₂, C(O)(CR⁷R⁸)_(a)N(R⁶)₂,S(O)_(e)(CR⁷R⁸)_(a)N(R⁶)₂, (CR⁷R⁸)_(a)R⁶, O(CR⁷R⁸)_(a)R⁶,N(R⁶)(CR⁷R⁸)_(a)R⁶, C(O)(CR⁷R⁸)_(a)R⁶ and S(O)_(e)(CR⁷R⁸)_(a)R⁶.
 30. Acompound of claim 24 wherein R is selected from the group consisting ofN(R⁶)(CR⁷R⁸)_(a)C(O)R⁶, (CR⁷R⁸)_(a)C(O)N(R⁶)₂,(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶), (CR⁷R⁸)_(a)(OR⁶), C(O)(CR⁷R⁸)_(a)N(R⁶)₂ andN(R⁶)(CR⁷R⁸)_(a)C(O)OR⁶.
 31. A compound of claim 25 wherein R isselected from the group consisting of N(R⁶)(CR⁷R⁸)_(a)C(O)R⁶,(CR⁷R⁸)_(a)C(O)N(R⁶)₂, (CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶), (CR⁷R⁸)_(a)(OR⁶),C(O)(CR⁷R⁸)_(a)N(R⁶)₂ and N(R⁶)(CR⁷R⁸)_(a)C(O)OR⁶.
 32. A compound ofclaim 26 wherein R is selected from the group consisting ofN(R⁶)(CR⁷R⁸)_(a)C(O)R⁶, (CR⁷R⁸)_(a)C(O)N(R⁶)₂,(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶), (CR⁷R⁸)_(a)(OR⁶), C(O)(CR⁷R⁸)_(a)N(R⁶)₂ andN(R⁶)(CR⁷R⁸)_(a)C(O)OR⁶.
 33. A compound of claim 27 wherein R isselected from the group consisting of N(R⁶)(CR⁷R⁸)_(a)C(O)R⁶,(CR⁷R⁸)_(a)C(O)N(R⁶)₂, (CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶), (CR⁷R⁸)_(a)(OR⁶),C(O)(CR⁷R⁸)_(a)N(R⁶)₂ and N(R⁶)(CR⁷R⁸)_(a)C(O)OR⁶.
 34. A compound ofclaim 28 wherein R is selected from the group consisting ofN(R⁶)(CR⁷R⁸)_(a)C(O)R⁶, (CR⁷R⁸)_(a)C(O)N(R⁶)₂,(CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶), (CR⁷R⁸)_(a)(OR⁶), C(O)(CR⁷R⁸)_(a)N(R⁶)₂ andN(R⁶)(CR⁷R⁸)_(a)C(O)OR⁶.
 35. A compound of claim 29 wherein R isselected from the group consisting of N(R⁶)(CR⁷R⁸)_(a)C(O)R⁶,(CR⁷R⁸)_(a)C(O)N(R⁶)₂, (CR⁷R⁸)_(a)C(O)N(OR⁶)(R⁶), (CR⁷R⁸)_(a)(OR⁶),C(O)(CR⁷R⁸)_(a)N(R⁶)₂ and N(R⁶)(CR⁷R⁸)_(a)C(O)OR⁶.
 36. A compound ofclaim 24 selected from the group consisting of5-[(3-hydroxyphenyl)ethynyl]-N-[(4-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide,N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-(phenylethynyl)nicotinamide,N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-[(4-methylphenyl)ethynyl]nicotinamide,5-[(3-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide,5-[(3-methoxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide,5-[(4-methoxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide,5-[(4-bromophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide,5-[(4-chlorophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide,5-[(2-chlorophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide,N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-{[4-(trifluoromethyl)phenyl]ethynyl}nicotinamide,5-[(2-bromophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide,5-[(2,4-difluorophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide,5-[(3-fluorophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide,N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-[(2-methylphenyl)ethynyl]nicotinamide,5-[(3-bromophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide,5-[(3-chlorophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide,5-[(3,5-dimethoxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide,5-[(4-methoxy-2-methylphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide,5-[(4-fluoro-3-methylphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide,5-[(3-hydroxyphenyl)ethynyl]-N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide,5-[(3-methoxyphenyl)ethynyl]-N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide,5-[(4-methoxyphenyl)ethynyl]-N-[methyl(4-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide,N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(phenylethynyl)nicotinamide,N-[(4-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3-hydroxyphenyl)ethynyl]nicotinamide,N-{[3-(acetylamino)phenyl](methyl)oxo-λ⁶-sulfanylidene}-5-[(3-hydroxyphenyl)ethynyl]nicotinamide,N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(phenylethynyl)nicotinamide,N-[(3-chlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3-hydroxyphenyl)ethynyl]nicotinamide,N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(phenylethynyl)nicotinamide,N-[(3,5-dichlorophenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3-hydroxyphenyl)ethynyl]nicotinamide,5-[(3-hydroxyphenyl)ethynyl]-N-[methyl(3-methylphenyl)oxo-λ⁶-sulfanylidene]nicotinamide,N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(phenylethynyl)nicotinamide,5-[(3-hydroxyphenyl)ethynyl]-N-[(3-methoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]nicotinamide,N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(phenylethynyl)nicotinamide,N-[(3,4-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3-hydroxyphenyl)ethynyl]nicotinamide,N-[(3,5-dimethylphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-(phenylethynyl)nicotinamide,N-[(3,4-dimethoxyphenyl)(methyl)oxo-λ⁶-sulfanylidene]-5-[(3-hydroxyphenyl)ethynyl]nicotinamide,(S)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-(phenylethynyl)nicotinamide,(S)-5-[(2-fluorophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide,(S)-5-[(4-chlorophenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide,(S)-5-[(3-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide,(S)-5-[(4-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide,(R)-5-[(3-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide,(S)-5-[(4-hydroxy-3-methylphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide,(S)-5-(1H-indol-6-ylethynyl)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide,(S)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-({4-[(2-thienylcarbonyl)amino]phenyl}ethynyl)nicotinamide,(S)-5-{[3-(acetylamino)phenyl]ethynyl}-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide,(S)-5-({4-[(2,6-difluorobenzoyl)amino]phenyl}ethynyl)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide,(S)-5-({4-[(4-fluorobenzoyl)amino]phenyl}ethynyl)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide,(S)-5-({4-[(4-methylbenzoyl)amino]phenyl}ethynyl)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide,(S)-5-({4-[(2-methylbenzoyl)amino]phenyl}ethynyl)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide,(S)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-({3-[(2-thienylcarbonyl)amino]phenyl}ethynyl)nicotinamide,(S)-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide,(S)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-({3-[(3-methylthienyl-2-carbonyl)amino]phenyl}ethynyl)nicotinamide,(S)-tert-butyl(3-{[5-({[methyl(oxo)phenyl-λ⁶-sulfanylidene]amino}carbonyl)pyridin-3-yl]ethynyl}phenyl)carbamateand(S)-5-({3-[(2-methylbenzoyl)amino]phenyl}ethynyl)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide.37. A compound of claim 30 selected from(S)-5-({4-[(2-methylbenzoyl)amino]phenyl}ethynyl)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide,(S)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-({3-[(2-thienylcarbonyl)amino]phenyl}ethynyl)nicotinamide,(S)-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide,(S)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]-5-({3-[(3-methylthienyl-2-carbonyl)amino]phenyl}ethynyl)nicotinamide(S)-tert-butyl(3-{[5-({[methyl(oxo)phenyl-λ⁶-sulfanylidene]amino}carbonyl)pyridin-3-yl]ethynyl}phenyl)carbamate,(S)-5-({3-[(2-methylbenzoyl)amino]phenyl}ethynyl)-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamideand(S)-5-{[3-(acetylamino)phenyl]ethynyl}-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide.38. A compound of claim 25 selected from the group consisting of(S)-tert-butyl(5-{[5-({[methyl(oxo)phenyl-λ⁶-sulfanylidene]amino}carbonyl)pyridin-3-yl]ethynyl}-1,3-thiazol-2-yl)carbamate,(S)-5-[(2-amino-1,3-thiazol-5-yl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamideand(S)-5-{[2-(benzoylamino)-1,3-thiazol-5-yl]ethynyl}-N-[methyl(oxo)phenyl-λ⁶sulfanylidene]nicotinamide.
 39. A compound according to claim 31 that is(S)-5-{[2-(benzoylamino)-1,3-thiazol-5-yl]ethynyl}-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide.40. A compound according to claim 26 selected from the group consistingof(S)-6-amino-5-[(3-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamideand(S)-6-amino-5-[(4-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide.41. A compound according to claim 27 that isS)-2-amino-5-[(3-hydroxyphenyl)ethynyl]-N-[methyl(oxo)phenyl-λ⁶-sulfanylidene]nicotinamide.42. A compound which is a substituted aroyl sulfoximine compound whichbinds to the tyrosine kinase receptor.
 43. The compound of claim 42wherein the substituted aryl moiety is represented by formula IV below:


44. The compound of claim 41 wherein said substituted aryl moiety isrepresented by formula V below

wherein B¹, R¹² and R¹³ are selected from the group consisting ofhalogen, nitro, hydroxy, hydrocarbyl, substituted hydrocarbyl, amide,thioamide, amine, thioether and cyano.